Azole derivatives, methods for producing the same, intermediate thereof, agro-horticultural agents

ABSTRACT

An azole derivative according to the invention is represented by Formula (XI) 
                         
wherein R 1  denotes a C 1 -C 6  alkyl group, a C 2 -C 6  alkenyl group or a C 2 -C 6  alkynyl group; R 2  denotes a C 1 -C 4  alkyl group; each Y denotes a halogen atom, a C 1 -C 4  alkyl group, a C 1 -C 4  haloalkyl group, a C 1 -C 4  alkoxy group, a C 1 -C 4  haloalkoxy group, a phenyl group, a cyano group or a nitro group; and m denotes 0 to 5; when m is 2 or more, each Y may be the same or different. As a result, an azole derivative contained as an active ingredient in an agro-horticultural agent having an excellent controlling effect on diseases can be provided.

This application is a Divisional of co-pending application Ser. No. 13/508,269 filed on May 25, 2012 which is a National Phase of PCT International Application No. PCT/JP/2010/007118 filed on Dec. 7, 2010, which claims the benefit of Japanese Application No. 2009-278593 filed Dec. 8, 2009. The entire contents of all of the above applications are hereby expressly incorporated by reference.

TECHNICAL FIELD

The present invention relates to a novel azole derivative. It also relates to an agro-horticultural agent and an industrial material protecting agent containing the derivative as an active ingredient as well as method for producing the derivatives.

BACKGROUND ART

A certain 2-substituted-benzyl-1-azolylmethylcyclopentanol derivative is known to have a biocidal activity (for example, see Patent Literatures 1 and 2).

Some compounds included in a 2-(halogenated hydrocarbon-substituted)-5-benzyl-1-azolylmethylcyclopentanol derivative are reported to exhibit anti-convulsive and antianxiolytic activities (see Patent Literature 3). Nevertheless, Patent Literature 3 contains no description with regard to agro-horticultural agents and industrial material protecting agents, and no specific disclosure of the compounds encompassed by the invention.

CITATION LIST Patent Literature

-   [PTL 1] Japanese Unexamined Patent Application Publication No.     01-93574 -   [PTL 2] Japanese Unexamined Patent Application Publication No.     01-186871 -   [PTL 3] German Patent Application, Publication No. 3902031     Specification -   [PTL 4] Japanese Unexamined Patent Application Publication No.     05-271197 -   [PTL 5] Japanese Unexamined Patent Application Publication No.     01-301664

SUMMARY OF INVENTION Technical Problem

Conventionally, an agro-horticultural pesticide having a low toxicity to humans and animals, capable of being handled safely, and exhibiting a high controlling effect on a wide range of plant diseases has been desired. Also, there has been a need for a plant growth regulator which regulates the growth of a variety of crops and horticultural plants thereby exhibiting yield-increasing and quality-improving effects, or an industrial material protecting agent which protects an industrial material from a wide range of hazardous microorganisms which invade such materials.

Accordingly, the present invention aims primarily at providing an agro-horticultural agent and an industrial material which fulfill the need described above.

Solution to Problem

To achieve the aim mentioned above, we made an extensive study on chemical structures and biological activities of 2-(halogenated hydrocarbon-substituted)-5-benzyl-1-azolylmethylcyclopentanol derivatives. As a result, we found that an azole derivative (specifically, 2-(halogenated hydrocarbon-substituted)-5-benzyl-1-azolylmethylcyclopentanol derivative) represented by Formula (I) shown below has an excellent activity, thus establishing the present invention. The invention is based on such novel findings, and includes the following inventive aspects.

Thus, an azole derivative according to the invention has a structure represented by Formula (I):

wherein each of R^(a) and R^(b) independently denotes a hydrogen atom, or a C₁-C₆ alkyl group, a C₂-C₆ alkenyl group or a C₂-C₆ alkynyl group; provided that R^(a) and R^(b) are not hydrogen atoms at the same time, and the hydrogen atoms of the alkyl group, the alkenyl group and the alkynyl group may be substituted with X^(a) or X^(b);

each of X^(a) and X^(b) denotes a halogen atom;

n^(a) denotes 0 or the number of X^(a)-substituted hydrogen atoms among the hydrogen atoms in R^(a);

n^(b) denotes 0 or the number of X^(b)-substituted hydrogen atoms among the hydrogen atoms in R^(b);

provided that “n^(a)+n^(b)” is 1 or more; when n^(a) is 2 or more, then each X^(a) may be same or different; when n^(b) is 2 or more, then each X^(b) may be same or different;

each Y denotes a halogen atom, a C₁-C₄ alkyl group, a C₁-C₄ haloalkyl group, a C₁-C₄ alkoxy group, a C₁-C₄ haloalkoxy group,

a phenyl group, a cyano group or a nitro group;

m denotes 0 to 5; when m is 2 or more, each Y may be same or different;

A denotes a nitrogen atom or a methyne group.

As a result of having the structure shown above, the azole derivative according to the invention is advantageous in exhibiting an excellent biocidal effect on a large number of microorganisms which induce diseases in plants.

The azole derivative according to the invention is preferable when each of the alkyl group, the alkenyl group and the alkynyl group in R^(a) and R^(b) in Formula (I) described above denotes a C₁-C₄ alkyl group, a C₂-C₄ alkenyl group and a C₂-C₄ alkynyl group; each of X^(a) and X^(b) denotes a fluorine atom, a chlorine atom or a bromine atom; each of n^(a) and n^(b) denotes 0 to 5; each Y denotes a halogen atom, a C₁-C₃ alkyl group, a C₁-C₃ haloalkyl group, a C₁-C₃ alkoxy group or a C₁-C₃ haloalkoxy group; m denotes 0 to 3; and A denotes a nitrogen atom.

The azole derivative according to the invention is preferable when the alkyl group in R^(a) and R^(b) in Formula (I) described above denotes a C₁-C₃ alkyl group; each of X^(a) and X^(b) denotes a chlorine atom or a bromine atom; each of n^(a) and n^(b) denotes 0 to 3; each Y denotes a halogen atom, a C₁-C₂ haloalkyl group or a C₁-C₂ haloalkoxy group; and m denotes 0 to 2.

The azole derivative according to the invention is preferable when all of n^(a), n^(b) and m in Formula (I) described above denote 0 to 1 and Y is a halogen atom.

The invention also includes the following intermediates of the azole derivatives.

The intermediate compound of the azole derivatives according to the invention is a 3-hydroxymethyl-2-oxocyclopentane carboxylic acid ester derivative represented by Formula (XI):

wherein R¹ denotes a C₁-C₆ alkyl group, a C₂-C₆ alkenyl group or a C₂-C₆ alkynyl group; and R² denotes a C₁-C₄ alkyl group.

Also, the intermediate compound of the azole derivatives according to the invention is an oxetane compound represented by Formula (XVI):

Also, the intermediate of the azole derivatives according to the invention is an oxetane sulfone ester derivative represented by Formula (XX):

wherein R³ denotes a lower alkyl group, or an optionally substituted phenyl group or naphthyl group.

The invention further includes the following inventions as methods for producing the azole derivatives shown above.

A method for producing the azole derivative according to the invention comprises a step for substituting a halogen atom-substitutable leaving group in an intermediate compound represented by Formula (II) with a halogen atom thereby obtaining a compound represented by Formula (Ia):

wherein each of R^(a) and R^(b) may be substituted with X^(a), X^(b), L^(a), L^(b) or Z; Z denotes a halogen atom; each of L^(a) and L^(b) denotes a halogen atom-substitutable leaving group; “n^(a1)+p^(a)” denotes 0 or the number of hydrogen atoms substituted with X^(a) or L^(a) or Z among the hydrogen atoms in R^(a); “n^(b1)+p^(b)” p denotes 0 or the number of hydrogen atoms substituted with X^(b) or L^(b) or Z among the hydrogen atoms in R^(b); “p^(a)+p^(b)” denotes 1 or more; when n^(a1) denotes 2 or more then each X^(a) may be same or different; when n^(b1) denotes 2 or more then each X^(b) may be same or different.

Furthermore, a method for producing the azole derivative according to the invention comprises a step for subjecting a carbonyl compound represented by Formula (V) to conversion into an oxirane thereby obtaining an oxirane derivative represented by Formula (III) which is then reacted with a compound represented by Formula (IV):

wherein M denotes a hydrogen atom or an alkaline metal.

Furthermore, a method for producing the azole derivative according to the invention comprises a step for subjecting an oxetane compound represented by Formula (XVI) to ring opening using a halogenic acid.

The invention further includes the following inventions as methods for producing intermediate compounds for the azole derivatives.

A method for producing an intermediate compound according to the invention comprises a step for reacting a 2-oxocyclopentane carboxylic acid ester derivative represented by Formula (XII) with formaldehyde or an equivalent thereof.

Also, a method for producing an intermediate compound according to the invention comprises a step for subjecting a 2,2-bishydroxymethyl cyclopentanol derivative represented by Formula (XIX) to conversion into an oxetane ring while converting into a sulfone ester.

Also, a method for producing an intermediate compound for an azole derivative according to the invention comprises a step for reducing the sulfone ester of an oxetane sulfone ester derivative represented by Formula (XX) to obtain an intermediate compound represented by Formula (XXI).

The invention also encompasses an agro-horticultural agent or an industrial material protecting agent containing as an active ingredient an azole derivative according to the invention.

In the specification and related matters, a symbol defining an identical functional group (or atom) in each formula is indicated as the identical symbol while omitting its detailed description. For example, an R^(a) shown in Formula (I) and an R^(a) shown in a different formula are identical. This understanding is not limited to R^(a), and is applicable also to other functional groups (or atoms).

Advantageous Effects of Invention

An azole derivative according to the invention has an excellent biocidal effect on a large number of microorganisms which induce diseases in plants. Therefore, an agro-horticultural agent containing the azole derivative according to the invention as an active ingredient can advantageously exhibit a high controlling effect on a wide range of plant diseases.

Moreover, the agro-horticultural agent containing the azole derivative according to the invention as an active ingredient can advantageously regulate the growth of a variety of crops and horticultural plants thereby increasing their yields while improving their qualities.

On the other hand, an industrial material protecting agent containing the azole derivative according to the invention as an active ingredient can further advantageously protect an industrial material from a wide range of hazardous microorganisms which invade such materials.

DESCRIPTION OF EMBODIMENTS

The embodiments in the best mode for carrying out the invention are described below. These embodiments are just examples of the representative embodiments of the invention and do not serve to allow the scope of the invention to be interpreted narrowly. The descriptions are made in the orders shown below.

1. 2-(Halogenated hydrocarbon-substituted)-5-benzyl-1-azolylmethylcyclopentanol derivatives

(1) X^(a), X^(b), n^(a) and n^(b)

(2) (R^(a))X^(a)n^(a) and (R^(b))X^(b)n^(b)

(3) Y and m

(4) A

(5) Stereoisomers

(6) Typical examples

2. Methods for producing 2-(Halogenated hydrocarbon-substituted)-5-benzyl-1-azolylmethylcyclopentanol derivatives

(1) Solvents

(2) Bases and acids

(3) First method for producing Compound (I)

(3-1) Step 1A

(3-2) Step 1B

(3-3) Step 1C

(3-3-1) Step 1C1

(3-3-2) Step 1C2

(3-3-3) Step 1C3

(3-4) Step 1D

(3-4-1) Step 1D1

(3-4-2) Step 1D2

(3-4-3) Step 1D3

(4) Second method for producing Compound (I)

(4-1) Step 2A

(4-1-1) Step 2A1

(4-1-2) Step 2A2

(4-2) Step 2B

(4-2-1) Step 2B1

(4-2-2) Step 2B2

(5) Third method for producing Compound (I)

(5-1) Step 3A

(5-1-1) Step 3A1

(5-1-2) Step 3A2

(6) Fourth method for producing Compound (I)

(6-1) Step 4A

(6-1-1) Step 4A1

(6-1-2) Step 4A2

(6-1-3) Step 4A3

(6-1) Step 4B

(6-2-1) Step 4B1

(6-2-2) Step 4B2

(6-2-3) Step 4B3

(6-2) Step 4C

(6-3-1) Step 4C1

(6-3-2) Step 4C2

(6-3-3) Step 4C3

3. Agro-horticultural agents and industrial material protecting agents

(1) Plant disease controlling effects

(2) Plant growth promoting effect

(3) Industrial material protecting effect

(4) Formulations

1. 2-(Halogenated hydrocarbon-substituted)-5-benzyl-1-azolylmethylcyclopentanol derivatives

A 2-(halogenated hydrocarbon-substituted)-5-benzyl-1-azolylmethylcyclopentanol derivative represented by Formula (I) shown below according to the invention (hereinafter referred to as Compound (I)) is described below. Compound (I) has a hydrocarbon substituent bound to 2-position of the cyclopentane ring which is a halogen-substituted hydrocarbon substituent. Compound (I) is a novel compound which has not been described in any reference.

The typical examples of respective symbols (R^(a), R^(b), X^(a), X^(b), n^(a), n^(b), Y, m, and A) in Compound (I) and described below. The respective symbols in Formulas which denote other compounds (R^(a1), R^(a2), R^(b1), R^(b2), X^(a1), X^(a2), X^(b1), X^(b2), n^(a1), n^(a2), n^(b1) and n^(b2)) have similar meanings as those indicated here (R^(a), R^(b), X^(a), X^(b), n^(a) and n^(b)).

(1) X^(a), X^(b), n^(a) and n^(b)

Each of X^(a) and X^(b) may for example be a halogen atom.

The halogen atom may for example be a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Among these, a fluorine atom, a chlorine atom and a bromine atom are preferred, with a chlorine atom being especially preferred.

n^(a) denotes 0 or the number of X^(a)-substituted hydrogen atoms in R^(a). n^(b) denotes 0 or the number of X^(b)-substituted hydrogen atoms in R^(b), n^(a) and n^(b) are preferably within the range of 0 to 5, more preferably 0 to 3, especially 0 to 1. Nevertheless, “n^(a)+n^(b)” is an integer of 1 or more. When n^(a) is 2 or more, then each X^(a) may be same or different. When n^(b) is 2 or more, then each X^(b) may be same or different.

(2) (R^(a))X^(a)n^(a) and (R^(b))X^(b)n^(b)

First, when n^(a) is 0, the following substituents may be exemplified as R^(a).

Hydrogen atom; provided that R^(a) and R^(b) are not hydrogen atoms at the same time. When R^(a) is a hydrogen atom, R^(a) is not substituted with X^(a). This understanding is not limited to R^(a), and is applicable also to R^(b).

C₁-C₆ Alkyl group: specifically, a methyl group, an ethyl group, a (1-methyl)ethyl group, a n-propyl group, a 1-methylpropyl group, 2-methylpropyl group, a n-butyl group, a 1-methylbutyl group, 2-methylbutyl group, a 1-ethylpropyl group and a 1,1-dimethylethyl group can be exemplified. Among these, a C₁-C₄ alkyl group is preferred, with C₁-C₃ alkyl group being especially preferred.

C₂-C₆ Alkenyl group: specifically, an ethenyl group,

a 1,2-dimethylethenyl group, a 4-methyl-1,3-butadienyl group, a 1-propenyl group, a 2-propenyl group, a 2-methyl-2-propenyl group, a 3-methyl-2-propenyl group, a 2-butenyl group, a 3-butenyl group

and 3-methyl-3-butenyl group can be exemplified. Among these, a C₂-C₄ alkenyl group is preferred.

C₂-C₆ Alkynyl group: specifically, an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-butynyl group and a 2-butynyl group can be exemplified.

Among these, a C₂-C₄ alkynyl group is preferred.

(R^(b))X^(b)n^(b) when n^(b) is 0 is similar to (R^(a))X^(a)n^(a) when n^(a) is 0.

When n^(a) is 1 to 3, the following substituents can be exemplified as (R^(a))X^(a)n^(a).

C₁-C₆ Alkyl group: specifically, a halogen-substituted C₁-C₆ alkyl group, such as a chloromethyl group, a dichloromethyl group, a trichloromethyl group, a 2-chloroethyl group, a 1-chloroethyl group, a 2,2-dichloroethyl group, a 1,2-dichloroethyl group, a 2,2,2-trichloroethyl group, a 3-chloropropyl group, a 2,3-dichloropropyl group, a 1-chloro-1-methylethyl group, 2-chloro-1-methylethyl group, a 2-chloropropyl group, a 4-chlorobutyl group, a 5-chloropentyl group, a fluoromethyl group,

a difluoromethyl group, a trifluoromethyl group, a 2-fluoroethyl group, a 1-fluoroethyl group, a 2,2-difluoroethyl group, a 1,2-difluoroethyl group, a 2,2,2-trifluoroethyl group, a 3-fluoropropyl group, a 2,3-difluoropropyl group, a 1-fluoro-1-methylethyl group, a 2-fluoro-1-methylethyl group, a 2-fluoropropyl group, a 3,3,3-trifluoropropyl group, a 2,2,3,3-tetrafluoropropyl group, a 2,2,3,3,3-pentafluoropropyl group,

a 4-fluorobutyl group, a 5-fluoropentyl group, a bromomethyl group, a dibromomethyl group, a tribromomethyl group, a 2-bromoethyl group, a 1-bromoethyl group, a 2,2-dibromoethyl group, a 1,2-dibromoethyl group, a 2,2,2-tribromoethyl group, a 3-bromopropyl group, a 2,3-dibromopropyl group, a 1-bromo-1-methylethyl group, a 2-bromo-1-methylethyl group, a 2-bromopropyl group, a 4-bromobutyl group, a 5-bromopentyl group, a iodomethyl group, a diiodomethyl group, a 2-iodoethyl group, a 1-iodoethyl group, a 2,2-diiodoethyl group, a 1,2-diiodoethyl group, a 2,2,2-triiodoethyl group, a 3-iodopropyl group, a 2,3-diiodopropyl group, a 1-iodo-1-methylethyl group, a 2-iodo-1-methylethyl group, a 2-iodopropyl group, a 4-iodobutyl group and the like can be exemplified. Among these, a C₁-C₄ alkyl group is preferred, with a C₁-C₃, alkyl group being especially preferred.

C₂-C₆ Alkenyl group: specifically, a halogen-substituted C₂-C₆ alkenyl group, such as a 2-chloroethenyl group, a 2,2-dichloroethenyl group, a 2-chloro-2-propenyl group, a 3,3-dichloro-2-propenyl group, a 2,3-dichloro-2-propenyl group, a 3,3-dichloro-2-methyl-2-propenyl group, a 3-chloro-2-butenyl group, a 2-fluoroethenyl group, a 2,2-difluoroethenyl group, a 2-fluoro-2-propenyl group, a 3,3-difluoro-2-propenyl group, a 2,3-difluoro-2-propenyl group, a 3,3-difluoro-2-methyl-2-propenyl group, a 3-fluoro-2-butenyl group, a 2-bromoethenyl group, a 2,2-dibromoethenyl group, a 2-bromo-2-propenyl group, a 3,3-dibromo-2-propenyl group, a 2,3-dibromo-2-propenyl group, a 3,3-dibromo-2-methyl-2-propenyl group, a 3-bromo-2-butenyl group, a 2-iodoethenyl group, a 2,2-diiodoethenyl group, a 2-iodo-2-propenyl group, a 3,3-diiodo-2-propenyl group, a 2,3-diiodo-2-propenyl group and the like can be exemplified. Among these, a C₂-C₄ alkenyl group is preferred.

C₂-C₆ Alkynyl group: specifically, a halogen-substituted C₂-C₆ alkynyl group, such as a 2-fluoroethynyl group, a 2-chloroethynyl group, a 3-fluoro-2-propynyl group, a 3-chloro-2-propynyl group, a 3-bromo-2-propynyl group and the like can be exemplified. Among these, a C₂-C₄ alkynyl group is preferred.

(R^(b))X^(b)n^(b) when n^(b) is 1 to 3 is similar to (R^(a))X^(a)n^(a) when n^(a) is 1 to 3.

(3) Y and m

The following substituents can be exemplified as Y.

Halogen atom: specifically, a chlorine atom, a fluorine atom, a bromine atom and an iodine atom can be exemplified.

C₁-C₄ Alkyl group: specifically, a methyl group, an ethyl group, a n-propyl group, a 1-methylethyl group, 2-methylpropyl group, a n-butyl group, a 1,1-dimethylethyl group and the like can be exemplified.

C₁-C₄ Haloalkyl group: specifically, a trifluoromethyl group, a 1,1,2,2,2-pentafluoroethyl group, a chloromethyl group, a trichloromethyl group, a bromomethyl group and the like can be exemplified.

C₁-C₄ Alkoxy group: specifically, a methoxy group, an ethoxy group, a n-propoxy group and the like can be exemplified.

C₁-C₄ Haloalkoxy group: specifically, a trifluoromethoxy group, a difluoromethoxy group, a 1,1,2,2,2-pentafluoroethoxy group, a 2,2,2-trifluoroethoxy group and the like can be exemplified.

Y may also be a phenyl group, a cyano group or a nitro group.

Y is preferably a halogen atom, a C₁-C₃ haloalkyl group, a C₁-C₃ haloalkoxy group, a C₁-C₃ alkyl group and a C₁-C₃ alkoxy group, with a halogen atom, a C₁-C₂ haloalkyl group and a C₁-C₂haloalkoxy group being especially preferred.

m denotes an integer of 0 to 5. When m is 2 or more, each Y may be same or different. m is preferably 0 to 3, and more preferably 0 to 2.

(4) A

A nitrogen atom or a methyne group can be exemplified as A. More preferably, A is a nitrogen atom.

(5) Stereoisomers

Compound (I) exists as a stereoisomer represented by Formula (I-C) or (I-T) (type C or type T). Compound (I) may be either one of the isomers, or a mixture thereof. In Formula shown below, the relative steric configuration of a cis type between the hydroxyl group in 1-position and the benzyl group in 5-position is referred to as (I-C), while the relative steric configuration of a trans type is referred to as (I-T).

(6) Typical Examples

Depending on the combination of (R^(a))X^(a)n^(a), (R^(b))X^(b)n^(b), Ym, A and isomers described above, the compounds indicated in Table 1 to Table 13 shown below can be exemplified as Compounds (1).

Each table can be understood as described below.

1) Columns of (R^(a))X^(a)n^(a)

(R^(a))X^(a)n^(a) is indicated as a single substituent. Unless R^(a) is a hydrogen atom, it should be understood that the hydrogen atom-deficient carbon atom on the left end of (R^(a))X^(a)n^(a) serves to the binding to the cyclopentane ring in Compound (I). A case having no halogen atom in (R^(a))X^(a)n^(a) here means n^(a)=0.

2) Columns of (R^(b))X^(b)n^(b)

(R^(b))X^(b)n^(b) is indicated as a single substituent. Unless R^(b) is a hydrogen atom, it should be understood that the hydrogen atom-deficient carbon atom on the left end of (R^(b))X^(b)n^(b) serves to the binding to the cyclopentane ring in Compound (I). A case having no halogen atom in the substituent here means n^(b)=0.

3) Columns of Ym

“-(hyphen)” indicates a non-substitution (m=0). The number before “-” indicates the binding position when regarding the carbon atom binding to the carbon atom binding to the cyclopentane ring as being in 1-position in the case having a substituent on a phenyl ring.

TABLE 1 Compound No. (R^(a))X^(a)n^(a 1)) (R^(b))X^(b)n^(b 2)) Ym ³⁾ A Type I-1 CH₃ CH₂Cl 4-Cl N C I-2 CH₃ CHCl₂ 4-Cl N C I-3 CH₃ CCl₃ 4-Cl N C I-4 CH₃ CH₂CH₂Cl 4-Cl N C I-5 CH₃ CHClCH₃ 4-Cl N C I-6 CH₃ CH₂CHCl₂ 4-Cl N C I-7 CH₃ CHClCH₂Cl 4-Cl N C I-8 CH₃ CH₂CCl₃ 4-Cl N C I-9 CH₃ CH₂CH₂CH₂Cl 4-Cl N C I-10 CH₃ CH₂CHClCH₂Cl 4-Cl N C I-11 CH₃ CCl(CH₃)CH₃ 4-Cl N C I-12 CH₃ CH(CH₂Cl)CH₃ 4-Cl N C I-13 CH₃ CH₂CH₂CH₂CH₂Cl 4-Cl N C I-14 CH₃ CH═CCl₂ 4-Cl N C I-15 CH₃ CH₂CCl═CH₂ 4-Cl N C I-16 CH₃ CH₂CH═CCl₂ 4-Cl N C I-17 CH₃ CH₂CCl═CHCl 4-Cl N C I-18 CH₃ CH₂CH═C(Cl)CH₃ 4-Cl N C I-19 CH₃ C≡CCl 4-Cl N C I-20 CH₃ CH₂F 4-Cl N C I-21 CH₃ CF₃ 4-Cl N C I-22 CH₃ CH₂CH₂F 4-Cl N C I-23 CH₃ CH₂CF₃ 4-Cl N C I-24 CH₃ CH═CF₂ 4-Cl N C I-25 CH₃ CH₂Br 4-Cl N C I-26 CH₃ CH₂CH₂Br 4-Cl N C I-27 CH₃ CHBrCH₃ 4-Cl N C I-28 CH₃ CH₂CHCl₂ 4-Cl N C I-29 CH₃ CHBrCH₂Br 4-Cl N C I-30 CH₃ CH₂CHBrCH₂Br 4-Cl N C I-31 CH₃ CBr(CH₃)CH₃ 4-Cl N C I-32 CH₃ CH(CH₂Br)CH₃ 4-Cl N C I-33 CH₃ CH₂CBr═CH₂ 4-Cl N C I-34 CH₃ CH₂C≡CBr 4-Cl N C I-35 CH₃ CH₂I 4-Cl N C I-36 CH₂CH₃ CH₂Cl 4-Cl N C I-37 CH₂CH₃ CH₂CH₂Cl 4-Cl N C I-38 CH₂CH₃ CHClCH₂Cl 4-Cl N C I-39 CH₂CH₃ CH₂CH₂CH₂Cl 4-Cl N C I-40 CH₂CH₃ CCl(CH₃)CH₃ 4-Cl N C I-41 CH₂CH₃ CH(CH₂Cl)CH₃ 4-Cl N C I-42 CH₂CH₃ CH═CCl₂ 4-Cl N C I-43 CH₂CH₃ CH₂CCl═CH₂ 4-Cl N C I-44 CH₂CH₃ CH₂CH═CCl₂ 4-Cl N C I-45 CH₂CH₃ CH₂F 4-Cl N C I-46 CH₂CH₃ CF₃ 4-Cl N C I-47 CH₂CH₃ CH₂CH₂F 4-Cl N C I-48 CH₂CH₃ CF(CH₃)CH₃ 4-Cl N C I-49 CH₂CH₃ CH₂Br 4-Cl N C

TABLE 2 Compound No. (R^(a))X^(a)n^(a 1)) (R^(b))X^(b)n^(b 2)) Ym ³⁾ A Type I-50 CH₂CH₃ CHBrCH₂Br 4-Cl N C I-51 CH₂CH₃ CBr(CH₃)CH₃ 4-Cl N C I-52 CH₂CH₃ CH═CBr₂ 4-Cl N C I-53 CH₂CH₃ CH₂CBr═CH₂ 4-Cl N C I-54 CH₂CH₃ CH₂I 4-Cl N C I-55 H CH₂Cl 4-Cl N C I-56 H CH₂CH₂Cl 4-Cl N C I-57 H CHClCH₂Cl 4-Cl N C I-58 H CH₂CH₂CH₂Cl 4-Cl N C I-59 H CCl(CH₃)CH₃ 4-Cl N C I-60 H CH(CH₂Cl)CH₃ 4-Cl N C I-61 H CH═CCl₂ 4-Cl N C I-62 H CH₂CCl═CH₂ 4-Cl N C I-63 H CH₂CH═CCl₂ 4-Cl N C I-64 H CH₂F 4-Cl N C I-65 H CF₃ 4-Cl N C I-66 H CH₂CH₂F 4-Cl N C I-67 H CF(CH₃)CH₃ 4-Cl N C I-68 H CH₂Br 4-Cl N C I-69 H CHBrCH₂Br 4-Cl N C I-70 H CBr(CH₃)CH₃ 4-Cl N C I-71 H CH═CBr₂ 4-Cl N C I-72 H CH₃CBr═CH₂ 4-Cl N C I-73 CH₃ CH₂Cl — N C I-74 CH₃ CH₂Cl 3-Cl N C I-75 CH₃ CH₂C1 3,4-Cl₂ N C I-76 CH₃ CH₂Cl 4-Br N C I-77 CH₃ CH₂C1 4-F N C I-78 CH₃ CH₂Cl 4-CF₃ N C I-79 CH₃ CH₂Cl 4-OCF₃ N C I-80 CH₃ CH₂C1 4-Me N C I-81 CH₃ CH₂Cl 4-OMe N C I-82 CH₃ CH₂Cl 4-Ph N C I-83 CH₃ CH₂Cl 4-CN N C I-84 CH₃ CH₂Cl 4-NO₂ N C I-85 CH₃ CH₂Cl 2-Cl N C I-86 CH₃ CH₂Cl 2-F N C I-87 CH₂ CH₂Cl 2,4-Cl₂ N C I-88 CH₃ CH₂Cl 2,4-F₂ N C I-89 CH₃ CH₂Cl 3-F,4-Cl N C I-90 CH₃ CH₂Cl 2-F,4-Cl N C I-91 CH₂CH₃ CH₂Cl 4-F N C I-92 CH₂CH₃ CH₂Cl 4-CF₃ N C I-93 CH₂CH₃ CH₂Cl 4-OCF₃ N C I-94 CH₂CH₃ CH₂Cl 4-Me N C I-95 CH₂CH₃ CH₂Cl 4-OMe N C I-96 CH₂CH₃ CH₂Cl 4-Ph N C I-97 CH₂CH₃ CH₂Cl — N C I-98 CH₂CH₃ CH₂Cl 2,4-F₂ N C

TABLE 3 Compound No. (R^(a))X^(a)n^(a 1)) (R^(b))X^(b)n^(b 2)) Ym ³⁾ A Type I-101 CH₂Cl CH₃ 4-Cl N C I-102 CHCl₂ CH₃ 4-Cl N C I-103 CCl₃ CH₃ 4-Cl N C I-104 CH₂CH₂Cl CH₃ 4-Cl N C I-105 CHClCH₃ CH₃ 4-Cl N C I-106 CH₂CHCl₂ CH₃ 4-Cl N C I-107 CHClCH₂Cl CH₃ 4-Cl N C I-108 CH₂CCl₃ CH₃ 4-Cl N C I-109 CH₂CH₂CH₂Cl CH₃ 4-Cl N C I-110 CH₂CHClCH₂Cl CH₃ 4-Cl N C I-111 CCl(CH₃)CH₃ CH₃ 4-Cl N C I-112 CH(CH₂Cl)CH₃ CH₃ 4-Cl N C I-113 CH₂CH₂CH₂CH₂Cl CH₃ 4-Cl N C I-114 CH═CCl₂ CH₃ 4-Cl N C I-115 CH₂CCl═CH₂ CH₃ 4-Cl N C I-116 CH₂CH═CCl₂ CH₃ 4-Cl N C I-117 CH₂CCl═CHCl CH₃ 4-Cl N C I-118 CH₂CH═C(Cl)CH₃ CH₃ 4-Cl N C I-119 C≡CHCl CH₃ 4-Cl N C I-120 CH₂F CH₃ 4-Cl N C I-121 CF₃ CH₃ 4-Cl N C I-122 CH₂CH₂F CH₃ 4-Cl N C I-123 CH₂CF₃ CH₃ 4-Cl N C I-124 CH═CF₂ CH₃ 4-Cl N C I-125 CH₂Br CH₃ 4-Cl N C I-126 CH₂CH₂Br CH₃ 4-Cl N C I-127 CHBrCH₃ CH₃ 4-Cl N C I-128 CH₂CHCl₂ CH₃ 4-Cl N C I-129 CHBrCH₂Br CH₃ 4-Cl N C I-130 CH₂CHBrCH₂Br CH₃ 4-Cl N C I-131 CBr(CH₃)CH₃ CH₃ 4-Cl N C I-132 CH(CH₂Br)CH₃ CH₃ 4-Cl N C I-133 CH₂CBr═CH₂ CH₃ 4-Cl N C I-134 CH₂C≡CHBr CH₃ 4-Cl N C I-135 CH₂I CH₃ 4-Cl N C I-136 CH₂Cl CH₂CH₃ 4-Cl N C I-137 CH₂CH₂Cl CH₂CH₃ 4-Cl N C I-138 CHClCH₂Cl CH₂CH₃ 4-Cl N C I-139 CH₂CH₂CH₂Cl CH₂CH₃ 4-Cl N C I-140 CCl(CH₃)CH₃ CH₂CH₃ 4-Cl N C I-141 CH(CH₂Cl)CH₃ CH₂CH₃ 4-Cl N C I-142 CH═CCl₂ CH₂CH₃ 4-Cl N C I-143 CH₂CCl═CH₂ CH₂CH₃ 4-Cl N C I-144 CH₂CH═CCl₂ CH₂CH₃ 4-Cl N C I-145 CH₂F CH₂CH₃ 4-Cl N C I-146 CF₃ CH₂CH₃ 4-Cl N C I-147 CH₂CH₂F CH₂CH₃ 4-Cl N C I-148 CF(CH₃)CH₃ CH₂CH₃ 4-Cl N C I-149 CH₂Br CH₂CH₃ 4-Cl N C

TABLE 4 Compound No. (R^(a))X^(a)n^(a 1)) (R^(b))X^(b)n^(b 2)) Ym ³⁾ A Type I-150 CHBrCH₂Br CH₂CH₃ 4-Cl N C I-151 CBr(CH₃)CH₃ CH₂CH₃ 4-Cl N C I-152 CH═CBr₂ CH₂CH₃ 4-Cl N C I-153 CH₂CBr═CH₂ CH₂CH₃ 4-Cl N C I-154 CH₂I CH₂CH₃ 4-Cl N C I-155 CH₂Cl H 4-Cl N C I-156 CH₂CH₂Cl H 4-Cl N C I-157 CHClCH₂Cl H 4-Cl N C I-158 CH₂CH₂CH₂Cl H 4-Cl N C I-159 CCl(CH₃)CH₃ H 4-Cl N C I-160 CH(CH₂Cl)CH₃ H 4-Cl N C I-161 CH═CCl₂ H 4-Cl N C I-162 CH₂CCl═CH₂ H 4-Cl N C I-163 CH₂CH═CCl₂ H 4-Cl N C I-164 CH₂F H 4-Cl N C I-165 CF₃ H 4-Cl N C I-166 CH₂CH₂F H 4-Cl N C I-167 CF(CH₃)CH₃ H 4-Cl N C I-168 CH₂Br H 4-Cl N C I-169 CHBrCH₂Br H 4-Cl N C I-170 CBr(CH₃)CH₃ H 4-Cl N C I-171 CH═CBr₂ H 4-Cl N C I-172 CH₂CBr═CH₂ H 4-Cl N C I-173 CH₂Cl CH₃ — N C I-174 CH₂Cl CH₃ 3-Cl N C I-175 CH₂Cl CH₃ 3,4-Cl₂ N C I-176 CH₂Cl CH₃ 4-Br N C I-177 CH₂Cl CH₃ 4-F N C I-178 CH₂Cl CH₃ 4-CF₃ N C I-179 CH₂Cl CH₃ 4-OCF₃ N C I-180 CH₂Cl CH₃ 4-Me N C I-181 CH₂Cl CH₃ 4-OMe N C I-182 CH₂Cl CH₃ 4-Ph N C I-183 CH₂Cl CH₃ 4-CN N C I-184 CH₂Cl CH₃ 4-NO₂ N C I-185 CH₂Cl CH₃ 2-Cl N C I-186 CH₂Cl CH₃ 2-F N C I-187 CH₂Cl CH₃ 2,4-Cl₂ N C I-188 CH₂Cl CH₃ 2,4-F₂ N C I-189 CH₂Cl CH₃ 3-F,4-Cl N C I-190 CH₂Cl CH₃ 2-F,4-Cl N C I-191 CH₂Cl CH₂CH₃ 4-F N C I-192 CH₂Cl CH₂CH₃ 4-CF₃ N C I-193 CH₂Cl CH₂CH₃ 4-OCF₃ N C I-194 CH₂Cl CH₂CH₃ 4-Me N C I-195 CH₂Cl CH₂CH₃ 4-OMe N C I-196 CH₂Cl CH₂CH₃ 4-Ph N C I-197 CH₂Cl CH₂CH₃ — N C I-198 CH₂Cl CH₂CH₃ 2,4-F₂ N C

TABLE 5 Compound No. (R^(a))X^(a)n^(a 1)) (R^(b))X^(b)n^(b 2)) Ym ³⁾ A Type I-201 CH(CH₃)CH₃ CH₂Cl 4-Cl N C I-202 CH₂CH₂CH₃ CH₂Cl 4-Cl N C I-203 CH₂Cl CH₂Cl 4-Cl N C I-204 CH₂CH₂Cl CH₂Cl 4-Cl N C I-205 CH(CH₃)CH₃ CH₂CH₂Cl 4-Cl N C I-206 CH₂CH₂CH₂CH₃ CH₂CH₂Cl 4-Cl N C I-207 CH₂Cl CH₂CH₂Cl 4-Cl N C I-208 CH₂CH₂Cl CH₂CH₂Cl 4-Cl N C I-209 CH(CH₃)CH₃ CH═CCl₂ 4-Cl N C I-210 CH₂CH₂CH₃ CH═CCl₂ 4-Cl N C I-211 CH(CH₃)CH₃ CH₂CCl═CH₂ 4-Cl N C I-212 CH₂CH₂CH₃ CH₂CCl═CH₂ 4-Cl N C I-213 CH(CH₃)CH₃ CF₃ 4-Cl N C I-214 CH₂CH₂CH₃ CF₃ 4-Cl N C I-215 CH(CH₃)CH₃ CH₂CF₃ 4-Cl N C I-216 CH₂CH₂CH₃ CH₂CF₃ 4-Cl N C I-217 CH₂CF₃ CH₂CF₃ 4-Cl N C I-218 CH₂CH₂CH₃ CH₂Br 4-Cl N C I-219 CH(CH₃)CH₃ CH₂Br 4-Cl N C I-220 CH₂CH₂CH₃ CH₂I 4-Cl N C I-221 CH(CH₃)CH₃ CH₂I 4-Cl N C I-222 CH₂Cl CH(CH₃)CH₃ 3-Cl N C I-223 CH₂Cl CH₂CH₂CH₃ 2-Cl N C I-224 CH₂Cl CH₂Cl 3,4-Cl₂ N C I-225 CH₂Cl CH₂CH₂Cl 4-F N C I-226 CH₂CH₂Cl CH(CH₃)CH₃ 3-F N C I-227 CH₂CH₂Cl CH₂CH₂CH₂CH₃ 4-CF₃ N C I-228 CH₂CH₂Cl CH₂Cl 4-OCF₃ N C I-229 CH₂CH₂Cl CH₂CH₂Cl 4-Ph N C I-230 CH═CCl₂ CH(CH₃)CH₃ 4-Me N C I-231 CH═CCl₂ CH₂CH₂CH₃ — N C I-232 CH₂CCl═CH₂ CH(CH₃)CH₃ 4-Br N C I-233 CH₂CCl═CH₂ CH₂CH₂CH₃ 4-Cl N C I-234 CF₃ CH(CH₃)CH₃ 4-Cl N C I-235 CF₃ CHCH₂CH₃ 4-Cl N C I-236 CH₂CF₃ CH(CH₃)CH₃ 4-Cl N C I-237 CH₂CF₃ CH₂CH₂CH₃ 4-Cl N C I-238 CH₂CF₃ CH₂CF₃ 4-Cl N C I-239 CH₂Br CH₂CH₂CH₃ 4-Cl N C I-240 CH₂Br CH(CH₃)CH₃ 4-Cl N C I-241 CH₂I CH₂CH₃CH₃ 4-Cl N C I-242 CH₂I CH(CH₃)CH₃ 4-Cl N C I-243 CH₂Cl CH₃ 4-Cl CH C I-244 CH₃ CH₂Cl 4-Cl CH C I-245 CH₂CH₃ CH₂Cl 4-Cl CH C I-246 CH(CH₃)CH₃ CH₂Cl 4-Cl CH C I-247 CH₂CH₂CH₃ CH₂Cl 4-Cl CH C I-248 CH₂Cl CH₂Cl 4-Cl CH C I-249 CH₂CH₂Cl CH₂Cl 4-Cl CH C I-250 CH(CH₃)CH₃ CH₂Cl 4-Cl CH C

TABLE 6 Compound No. (R^(a))X^(a)n^(a 1)) (R^(b))X^(b)n^(b 2)) Ym ³⁾ A Type I-251 CH₂CH₂CH₂CH₃ CH₂Cl 4-Cl CH C I-252 CH═CCl₂ CH₂Cl 4-Cl CH C I-253 CH₂CCl═CH₂ CH₂Cl 4-Cl CH C I-254 CF₃ CH₂Cl 3-Cl CH C I-255 CH₂CF₃ CH₂Cl 2-Cl CH C I-256 CH₂Br CH₂Cl 3,4-Cl₂ CH C I-257 CH₃ CH₂CH₂Cl 4-F CH C I-258 CH₂CH₃ CH₂CH₂Cl 3-F CH C I-259 CH(CH₃)CH₃ CH₂CH₂Cl 4-CF₃ CH C I-260 CH₂CH₂CH₃ CH₂CH₂Cl 4-OCF₃ CH C I-261 CH₂Cl CH₃ 4-Ph CH C I-262 CH₂Cl CH₂CH₃ 4-Me CH C I-263 CH₂Cl CH(CH₃)CH₃ 3-Br CH C I-264 CH₂Cl CH₂CH₂CH₃ 4-Br CH C I-265 CH₂F CH₂F 4-Cl CH C I-266 CH₂Cl CH₂CH₂Cl 4-Cl CH C I-267 CH₂Cl CH(CH₃)CH₃ 4-Cl CH C I-268 CH₂Cl CH₂CH₂CH₂CH₃ 4-Cl CH C I-269 CH₂Cl CH═CCl₂ 4-Cl CH C I-270 CH₂Cl CH₂CCl═CH₂ 4-Cl CH C I-271 CH₂Cl CF₃ 4-Cl CH C I-272 CH₂Cl CH₂CF₃ 4-Cl CH C I-273 CH₂Cl CH₂Br 4-Cl CH C I-274 CH₂CH₂Cl CH₃ 4-Cl CH C I-275 CH₂CH₂Cl CH₂CH₃ 4-Cl CH C I-276 CH₂CH₂Cl CH(CH₃)CH₃ 4-Cl CH C I-277 CH₂CH₂Cl CH₂CH₂CH₃ 4-Cl CH C I-278 CH₃ CH₂Cl 3-Cl CH C I-279 CH₃ CH₂Cl 2-Cl CH C I-280 CH₃ CH₂Cl 4-F CH C I-281 CH₃ CH₂Cl 3-F CH C I-282 CH₃ CH₂Cl 2-F CH C I-283 CH₃ CH₂Cl 4-OCF₃ CH C I-284 CH₃ CH₂Cl 4-CF₃ CH C I-285 CH₃ CH₂Cl 2,4-Cl₂ CH C I-286 CH₃ CH₂Cl 2,4-F₂ CH C I-287 CH₃ CH₂Cl 4-Ph CH C I-288 CH₃ CH₂Cl 4-Br CH C I-289 CH₂Cl CH₃ 3-Cl CH C I-290 CH₃Cl CH₃ 2-Cl CH C I-291 CH₂Cl CH₃ 4-F CH C I-292 CH₂Cl CH₃ 3-F CH C I-293 CH₂Cl CH₃ 2-F CH C I-294 CH₂Cl CH₃ 4-OCF₃ CH C I-295 CH₂Cl CH₃ 4-CF₃ CH C I-296 CH₂Cl CH₃ 2,4-Cl₂ CH C I-297 CH₂Cl CH₃ 2,4-F₂ CH C I-298 CH₂Cl CH₃ 4-Ph CH C I-299 CH₂Cl CH₃ 4-Br CH C

TABLE 7 Compound No. (R^(a))X^(a)n^(a 1)) (R^(b))X^(b)n^(b 2)) Ym ³⁾ A Type I-301 CH₃ CH₂Cl 4-Cl N T I-302 CH₃ CHCl₂ 4-Cl N T I-303 CH₃ CCl₃ 4-Cl N T I-304 CH₃ CH₂CH₂Cl 4-Cl N T I-305 CH₃ CHClCH₃ 4-Cl N T I-306 CH₃ CH₂CHCl₂ 4-Cl N T I-307 CH₃ CHClCH₂Cl 4-Cl N T I-308 CH₃ CH₂CCl₃ 4-Cl N T I-309 CH₃ CH₂CH₂CH₂Cl 4-Cl N T I-310 CH₃ CH₂CHClCH₂Cl 4-Cl N T I-311 CH₃ CCl(CH₃)CH₃ 4-Cl N T I-312 CH₃ CH(CH₂Cl)CH₃ 4-Cl N T I-313 CH₃ CH₂CH₂CH₂CH₂Cl 4-Cl N T I-314 CH₃ CH═CCl₂ 4-Cl N T I-315 CH₃ CH₂CCl═CH₂ 4-Cl N T I-316 CH₃ CH₂CH═CCl₂ 4-Cl N T I-317 CH₃ CH₂CCl═CHCl 4-Cl N T I-318 CH₃ CH₂CH═C(Cl)CH₃ 4-Cl N T I-319 CH₃ C≡CCl 4-Cl N T I-320 CH₃ CH₂F 4-Cl N T I-321 CH₃ CF₃ 4-Cl N T I-322 CH₃ CH₂CH₂F 4-Cl N T I-323 CH₃ CH₂CF₃ 4-Cl N T I-324 CH₃ CH═CF₂ 4-Cl N T I-325 CH₃ CH₂Br 4-Cl N T I-326 CH₃ CH₂CH₂Br 4-Cl N T I-327 CH₃ CHBrCH₃ 4-Cl N T I-328 CH₃ CH₂CHCl₂ 4-Cl N T I-329 CH₃ CHBrCH₂Br 4-Cl N T I-330 CH₃ CH₂CHBrCH₂Br 4-Cl N T I-331 CH₃ CBr(CH₃)CH₃ 4-Cl N T I-332 CH₃ CH(CH₂Br)CH₃ 4-Cl N T I-333 CH₃ CH₂CBr═CH₂ 4-Cl N T I-334 CH₃ CH₂C≡CBr 4-Cl N T I-335 CH₃ CH₂I 4-Cl N T I-336 CH₂CH₃ CH₂Cl 4-Cl N T I-337 CH₂CH₃ CH₂CH₂Cl 4-Cl N T I-338 CH₂CH₃ CHClCH₂Cl 4-Cl N T I-339 CH₂CH₃ CH₂CH₂CH₂Cl 4-Cl N T I-340 CH₂CH₃ CCl(CH₃)CH₃ 4-Cl N T I-341 CH₂CH₃ CH(CH₂Cl)CH₃ 4-Cl N T I-342 CH₂CH₃ CH═CCl₂ 4-Cl N T I-343 CH₂CH₃ CH₂CCl═CH₂ 4-Cl N T I-344 CH₂CH₃ CH₂CH═CCl₂ 4-Cl N T I-345 CH₂CH₃ CH₂F 4-Cl N T I-346 CH₂CH₃ CF₃ 4-Cl N T I-347 CH₂CH₃ CH₂CH₂F 4-Cl N T I-348 CH₂CH₃ CF(CH₃)CH₃ 4-Cl N T I-349 CH₂CH₃ CH₂Br 4-Cl N T

TABLE 8 Compound No. (R^(a))X^(a)n^(a 1)) (R^(b))X^(b)n^(b 2)) Ym ³⁾ A Type I-350 CH₂CH₃ CHBrCH₂Br 4-Cl N T I-351 CH₂CH₃ CBr(CH₃)CH₃ 4-Cl N T I-352 CH₂CH₃ CH═CBr₂ 4-Cl N T I-353 CH₂CH₃ CH₂CBr═CH₂ 4-Cl N T I-354 CH₂CH₃ CH₂I 4-Cl N T I-355 H CH₂Cl 4-Cl N T I-356 H CH₂CH₂Cl 4-Cl N T I-357 H CHClCH₂Cl 4-Cl N T I-358 H CH₂CH₂CH₂Cl 4-Cl N T I-359 H CCl(CH₃)CH₃ 4-Cl N T I-360 H CH(CH₂Cl)CH₃ 4-Cl N T I-361 H CH═CCl₂ 4-Cl N T I-362 H CH₂CCl═CH₂ 4-Cl N T I-363 H CH₂CH═CCl₂ 4-Cl N T I-364 H CH₂F 4-Cl N T I-365 H CF₃ 4-Cl N T I-366 H CH₂CH₂F 4-Cl N T I-367 H CF(CH₃)CH₃ 4-Cl N T I-368 H CH₂Br 4-Cl N T I-369 H CHBrCH₂Br 4-Cl N T I-370 H CBr(CH₃)CH₃ 4-Cl N T I-371 H CH═CBr2 4-Cl N T I-372 H CH₂CBr═CH₂ 4-Cl N T I-373 CH₃ CH₂Cl — N T I-374 CH₃ CH₂Cl 3-Cl N T I-375 CH₃ CH₂Cl 3,4-Cl₂ N T I-376 CH₃ CH₂Cl 4-Br N T I-377 CH₃ CH₂Cl 4-F N T I-378 CH₃ CH₂Cl 4-CF₃ N T I-379 CH₃ CH₂Cl 4-OCF₃ N T I-380 CH₃ CH₂Cl 4-Me N T I-381 CH₃ CH₂Cl 4-OMe N T I-382 CH₃ CH₂Cl 4-Ph N T I-383 CH₃ CH₂Cl 4-CN N T I-384 CH₃ CH₂Cl 4-NO₂ N T I-385 CH₃ CH₂Cl 2-Cl N T I-386 CH₃ CH₂Cl 2-F N T I-387 CH₃ CH₂Cl 2,4-Cl₂ N T I-388 CH₃ CH₂Cl 2,4-F₂ N T I-389 CH₃ CH₂Cl 3-F,4-Cl N T I-390 CH₃ CH₂Cl 2-F,4-Cl N T I-391 CH₂CH₃ CH₂Cl 4-F N T I-392 CH₂CH₃ CH₂Cl 4-CF₃ N T I-393 CH₂CH₃ CH₂Cl 4-OCF₃ N T I-394 CH₂CH₃ CH₂Cl 4-Me N T I-395 CH₂CH₃ CH₂Cl 4-OMe N T I-396 CH₂CH₃ CH₂Cl 4-Ph N T I-397 CH₂CH₃ CH₂Cl — N T I-398 CH₂CH₃ CH₂Cl 2,4-F₂ N T

TABLE 9 Compound No. (R^(a))X^(a)n^(a 1)) (R^(b))X^(b)n^(b 2)) Ym ³⁾ A Type I-401 CH₂Cl CH₃ 4-Cl N T I-402 CHCl₂ CH₃ 4-Cl N T I-403 CCl₃ CH₃ 4-Cl N T I-404 CH₂CH₂Cl CH₃ 4-Cl N T I-405 CHClCH₃ CH₃ 4-Cl N T I-406 CH₂CHCl₂ CH₃ 4-Cl N T I-407 CHClCH₂Cl CH₃ 4-Cl N T I-408 CH₂CCl₃ CH₃ 4-Cl N T I-409 CH₂CH₂CH₂Cl CH₃ 4-Cl N T I-410 CH₂CHClCH₂Cl CH₃ 4-Cl N T I-411 CCl(CH₃)CH₃ CH₃ 4-Cl N T I-412 CH(CH₂Cl)CH₃ CH₃ 4-Cl N T I-413 CH₂CH₂CH₂CH₂Cl CH₃ 4-Cl N T I-414 CH═CCl₂ CH₃ 4-Cl N T I-415 CH₂CCl═CH₂ CH₃ 4-Cl N T I-416 CH₂CH═CCl₂ CH₃ 4-Cl N T I-417 CH₂CCl═CHCl CH₃ 4-Cl N T I-418 CH₂CH═C(C1)CH₃ CH₃ 4-Cl N T I-419 C≡CCl CH₃ 4-Cl N T I-420 CH₂F CH₃ 4-Cl N T I-421 CF₃ CH₃ 4-Cl N T I-422 CH₂CH₂F CH₃ 4-Cl N T I-423 CH₂CF₃ CH₃ 4-Cl N T I-424 CH═CF₂ CH₃ 4-Cl N T I-425 CH₂Br CH₃ 4-Cl N T I-426 CH₂CH₂Br CH₃ 4-Cl N T I-427 CHBrCH₃ CH₃ 4-Cl N T I-428 CH₂CHCl₂ CH₃ 4-Cl N T I-429 CHBrCH₂Br CH₃ 4-Cl N T I-430 CH₂CHBrCH₂Br CH₃ 4-Cl N T I-431 CBr(CH₃)CH₃ CH₃ 4-Cl N T I-432 CH(CH₂Br)CH₃ CH₃ 4-Cl N T I-433 CH₂CBr═CH₂ CH₃ 4-Cl N T I-434 CH₂C═CBr CH₃ 4-Cl N T I-435 CH₂I CH₃ 4-Cl N T I-436 CH₂Cl CH₂CH₃ 4-Cl N T I-437 CH₂CH₂Cl CH₂CH₃ 4-Cl N T I-438 CHClCH₂Cl CH₂CH₃ 4-Cl N T I-439 CH₂CH₂CH₂Cl CH₂CH₃ 4-Cl N T I-440 CCl(CH₃)CH₃ CH₂CH₃ 4-Cl N T I-441 CH(CH₂Cl)CH₃ CH₂CH₃ 4-Cl N T I-442 CH═CCl₂ CH₂CH₃ 4-Cl N T I-443 CH₂CCl═CH₂ CH₂CH₃ 4-Cl N T I-444 CH₂CH═CCl₂ CH₂CH₃ 4-Cl N T I-445 CH₂F CH₂CH₃ 4-Cl N T I-446 CF₃ CH₂CH₃ 4-Cl N T I-447 CH₂CH₂F CH₂CH₃ 4-Cl N T I-448 CF(CH₃)CH₃ CH₂CH₃ 4-Cl N T I-449 CH₂Br CH₂CH₃ 4-Cl N T

TABLE 10 Compound No. (R^(a))X^(a)n^(a 1)) (R^(b))X^(b)n^(b 2)) Ym ³⁾ A Type I-450 CHBrCH₂Br CH₂CH₃ 4-Cl N T I-451 CBr(CH₃)CH₃ CH₂CH₃ 4-Cl N T I-452 CH═CBr₂ CH₂CH₃ 4-Cl N T I-453 CH₂CBr═CH₂ CH₂CH₃ 4-Cl N T I-454 CH₂I CH₂CH₃ 4-Cl N T I-455 CH₂Cl H 4-Cl N T I-456 CH₂CH₂Cl H 4-Cl N T I-457 CHClCH₂Cl H 4-Cl N T I-458 CH₂CH₂CH₂Cl H 4-Cl N T I-459 CCl(CH₃)CH₃ H 4-Cl N T I-460 CH(CH₂Cl)CH₃ H 4-Cl N T I-461 CH═CCl₂ H 4-Cl N T I-462 CH₂CCl═CH₂ H 4-Cl N T I-463 CH₂CH═CCl₂ H 4-Cl N T I-464 CH₂F H 4-Cl N T I-465 CF₃ H 4-Cl N T I-466 CH₂CH₂F H 4-Cl N T I-467 CF(CH₃)CH₃ H 4-Cl N T I-468 CH₂Br H 4-Cl N T I-469 CHBrCH₂Br H 4-Cl N T I-470 CBr(CH₃)CH₃ H 4-Cl N T I-471 CH═CBr₂ H 4-Cl N T I-472 CH₂CBr═CH₂ H 4-Cl N T I-473 CH₂Cl CH₃ — N T I-474 CH₂Cl CH₃ 3-Cl N T I-475 CH₂Cl CH₃ 3,4-Cl₂ N T I-476 CH₂Cl CH₃ 4-Br N T I-477 CH₂Cl CH₃ 4-F N T I-478 CH₂Cl CH₃ 4-CF₃ N T I-479 CH₂Cl CH₃ 4-OCF₃ N T I-480 CH₂Cl CH₃ 4-Me N T I-481 CH₂Cl CH₃ 4-OMe N T I-482 CH₂Cl CH₃ 4-Ph N T I-483 CH₂Cl CH₃ 4-CN N T I-484 CH₂Cl CH₃ 4-NO₂ N T I-485 CH₂Cl CH₃ 2-Cl N T I-486 CH₂Cl CH₃ 2-F N T I-487 CH₂Cl CH₃ 2,4-Cl₂ N T I-488 CH₂Cl CH₃ 2,4-F₂ N T I-489 CH₂Cl CH₃ 3-F,4-Cl N T I-490 CH₂Cl CH₃ 2-F,4-Cl N T I-491 CH₂Cl CH₂CH₃ 4-F N T I-492 CH₂Cl CH₂CH₃ 4-CF₃ N T I-493 CH₂Cl CH₂CH₃ 4-OCF₃ N T I-494 CH₂Cl CH₂CH₃ 4-Me N T I-495 CH₂Cl CH₂CH₃ 4-OMe N T I-496 CH₂Cl CH₂CH₃ 4-Ph N T I-497 CH₂Cl CH₂CH₃ — N T I-498 CH₂Cl CH₂CH₃ 2,4-F₂ N T

TABLE 11 Compound No. (R^(a))X^(a)n^(a 1)) (R^(b))X^(b 2)) Ym ³⁾ A Type I-501 CH(CH₃)CH₃ CH₂Cl 4-Cl N T I-502 CH₂CH₂CH₃ CH₂Cl 4-Cl N T I-503 CH₂Cl CH₂Cl 4-Cl N T I-504 CH₂CH₂Cl CH₂Cl 4-Cl N T I-505 CH(CH₃)CH₃ CH₂CH₂Cl 4-Cl N T I-506 CH₂CH₂CH₂CH₃ CH₂CH₂Cl 4-Cl N T I-507 CH₂Cl CH₂CH₂Cl 4-Cl N T I-508 CH₂CH₂Cl CH₂CH₂Cl 4-Cl N T I-509 CH(CH₃)CH₃ CH═CCl₂ 4-Cl N T I-510 CH₂CH₂CH₃ CH═CCl₂ 4-Cl N T I-511 CH(CH₃)CH₃ CH₂CCl═CH₂ 4-Cl N T I-512 CH₂CH₂CH₃ CH₂CCl═CH₂ 4-Cl N T I-513 CH(CH₃)CH₃ CF₃ 4-Cl N T I-514 CH₂CH₂CH₃ CF₃ 4-Cl N T I-515 CH(CH₃)CH₃ CH₂CF₃ 4-Cl N T I-516 CH₂CH₂CH₃ CH₂CF₃ 4-Cl N T I-517 CH₂CF₃ CH₂CF₃ 4-Cl N T I-518 CH₂CH₂CH₃ CH₂Br 4-Cl N T I-519 CH(CH₃)CH₃ CH₂Br 4-Cl N T I-520 CH₃CH₂CH₃ CH₂I 4-Cl N T I-521 CH(CH₃)CH₃ CH₂I 4-Cl N T I-522 CH₂Cl CH(CH₃)CH₃ 3-Cl N T I-523 CH₂Cl CH₂CH₂CH₃ 2-Cl N T I-524 CH₂Cl CH₂Cl 3,4-Cl₂ N T I-525 CH₂Cl CH₂CH₂Cl 4-F N T I-526 CH₂CH₂Cl CH(CH₃)CH₃ 3-F N T I-527 CH₂CH₂Cl CH₂CH₂CH₂CH₃ 4-CF₃ N T I-528 CH₂CH₂Cl CH₂Cl 4-OCF₃ N T I-529 CH₂CH₂Cl CH₂CH₃Cl 4-Ph N T I-530 CH═CCl₂ CH(CH₃)CH₃ 4-Me N T I-531 CH═CCl₂ CH₂CH₂CH₃ — N T I-532 CH₂CCl═CH₂ CH(CH₃)CH₃ 4-Br N T I-533 CH₂CCl═CH₂ CH₂CH₂CH₃ 4-Cl N T I-534 CF₃ CH(CH₃)CH₃ 4-Cl N T I-535 CF₃ CH₂CH₂CH₃ 4-Cl N T I-536 CH₂CF₃ CH(CH₃)CH₃ 4-Cl N T I-537 CH₂CF₃ CH₂CH₂CH₃ 4-Cl N T I-538 CH₂CF₃ CH₂CF₃ 4-Cl N T I-539 CH₂Br CH₂CH₂CH₃ 4-Cl N T I-540 CH₂Br CH(CH₃)CH₃ 4-Cl N T I-541 CH₂I CH₂CH₂CH₃ 4-Cl N T I-542 CH₂I CH(CH₃)CH₃ 4-Cl N T I-543 CH₂Cl CH₃ 4-Cl CH T I-544 CH₃ CH₂Cl 4-Cl CH T I-545 CH₂CH₃ CH₂Cl 4-Cl CH T I-546 CH(CH₃)CH₃ CH₂Cl 4-Cl CH T I-547 CH₂CH₂CH₃ CH₂Cl 4-Cl CH T I-548 CH₂Cl CH₂Cl 4-Cl CH T I-549 CH₂CH₂Cl CH₂Cl 4-Cl CH T I-550 CH(CH₃)CH₃ CH₂Cl 4-Cl CH T

TABLE 12 Compound No. (R^(a))X^(a)n^(a 1)) (R^(b))X^(b)n^(b 2)) Ym ³⁾ A Type I-551 CH₂CH₂CH₂CH₃ CH₂Cl 4-Cl CH T I-552 CH═CCl₂ CH₂Cl 4-Cl CH T I-553 CH₂CCl═CH₂ CH₂Cl 4-Cl CH T I-554 CF₃ CH₂Cl 3-Cl CH T I-555 CH₂CF₃ CH₂Cl 2-Cl CH T I-556 CH₂Br CH₂Cl 3,4-Cl₂ CH T I-557 CH₃ CH₂CH₂Cl 4-F CH T I-558 CH₂CH₃ CH₂CH₂Cl 3-F CH T I-559 CH(CH₃)CH₃ CH₂CH₂Cl 4-CF₃ CH T I-560 CH₂CH₂CH₃ CH₂CH₂Cl 4-OCF₃ CH T I-561 CH₂Cl CH₃ 4-Ph CH T I-562 CH₂Cl CH₂CH₃ 4-Me CH T I-563 CH₃Cl CH(CH₃)CH₃ 3-Br CH T I-564 CH₂Cl CH₂CH₂CH₃ 4-Br CH T I-565 CH₂Cl CH₂Cl 4-Cl CH T I-566 CH₂Cl CH₂CH₂Cl 4-Cl CH T I-567 CH₂Cl CH(CH₃)CH₃ 4-Cl CH T I-568 CH₂Cl CH₂CH₂CH₂CH₃ 4-Cl CH T I-569 CH₂Cl CH═CCl₂ 4-Cl CH T I-570 CH₂Cl CH₂CCl═CH₂ 4-Cl CH T I-571 CH₂Cl CF₃ 4-Cl CH T I-572 CH₂Cl CH₂CF₃ 4-Cl CH T I-573 CH₂Cl CH₂Br 4-Cl CH T I-574 CH₂CH₂Cl CH₃ 4-Cl CH T I-575 CH₂CH₂Cl CH₂CH₃ 4-Cl CH T I-576 CH₂CH₂Cl CH(CH₃)CH₃ 4-Cl CH T I-577 CH₂CH₂Cl CH₂CH₂CH₃ 4-Cl CH T I-578 CH₃ CH₂Cl 3-Cl CH C I-579 CH₃ CH₂Cl 2-Cl CH C I-580 CH₃ CH₂Cl 4-F CH C I-581 CH₃ CH₂Cl 3-F CH C I-582 CH₃ CH₂Cl 2-F CH C I-583 CH₃ CH₂Cl 4-OCF₃ CH C I-584 CH₃ CH₂Cl 4-CF₃ CH C I-585 CH₃ CH₂Cl 2,4-Cl₂ CH C I-586 CH₃ CH₂Cl 2,4-F₂ CH C I-587 CH₃ CH₂Cl 4-Ph CH C I-588 CH₃ CH₂Cl 4-Br CH C I-589 CH₂Cl CH₃ 3-Cl CH C I-590 CH₂Cl CH₃ 2-Cl CH C I-591 CH₂Cl CH₃ 4-F CH C I-592 CH₂Cl CH₃ 3-F CH C I-593 CH₂Cl CH₃ 2-F CH C I-594 CH₂Cl CH₃ 4-OCF₃ CH C I-595 CH₂Cl CH₃ 4-CF₃ CH C I-596 CH₂Cl CH₃ 2,4-Cl₂ CH C I-597 CH₂Cl CH₃ 2,4-F₂ CH C I-598 CH₂Cl CH₃ 4-Ph CH C I-599 CH₂Cl CH₃ 4-Br CH C

TABLE 13 Compound No. (R^(a))X^(a)n^(a) (R^(b))X^(b)n^(b) Ym A Type I-601 CH₃ CH₂Br 4-F N C I-602 CH₃ CH₂Br — N C I-603 CH₃ CH₂Br 3-Cl N C I-604 CH₃ CH₂Br 2-Cl N C I-605 CH₃ CH₂Br 3-F N C I-606 CH₃ CH₂Br 2-F N C I-607 CH₃ CH₂Br 4-OCF₃ N C I-608 CH₃ CH₂Br 4-CF₃ N C I-609 CH₃ CH₂Br 4-Me N C I-610 CH₂CH₃ CH₂Br 4-Cl N C I-611 CH₂CH₃ CH₂Br 4-F N C I-612 CH₂CH₃ CH₂Br — N C I-613 CH₃ CH₂Br 4-F N T I-614 CH₃ CH₂Br — N T I-615 CH₃ CH₂Br 3-Cl N T I-616 CH₃ CH₂Br 2-Cl N T I-617 CH₃ CH₂Br 3-F N T I-618 CH₃ CH₂Br 2-F N T I-619 CH₃ CH₂Br 4-OCF₃ N T I-620 CH₃ CH₂Br 4-CF₃ N T I-621 CH₃ CH₂Br 4-Me N T I-622 CH₂CH₃ CH₂Br 4-Cl N T I-623 CH₂CH₃ CH₂Br 4-F N T I-624 CH₂CH₃ CH₂Br — N T I-625 CH₂Br CH₃ 4-F CH C I-626 CH₂Br CH₃ — CH C I-627 CH₂Br CH₃ 3-Cl CH C I-628 CH₂Br CH₃ 2-Cl CH C I-629 CH₂Br CH₃ 3-F N C I-630 CH₂Br CH₃ 2-F N C I-631 CH₂Br CH₃ 4-OCF₃ CH C I-632 CH₂Br CH₃ 4-CF₃ CH C I-633 CH₂Br CH₃ 4-Me CH C I-634 CH₂Br CH₂CH₃ 4-Cl CH C I-635 CH₂Br CH₂CH₃ 4-F CH C I-636 CH₂Br CH₂CH₃ — CH C I-637 CH₂Br CH₃ 4-F CH T I-638 CH₂Br CH₃ — CH T I-639 CH₂Br CH₃ 3-Cl CH T I-640 CH₂Br CH₃ 2-Cl CH T I-641 CH₂Br CH₃ 3-F N T I-642 CH₂Br CH₃ 2-F N T I-643 CH₂Br CH₃ 4-OCF₃ CH T I-644 CH₂Br CH₃ 4-CF₃ CH T I-645 CH₂Br CH₃ 4-Me CH T I-646 CH₂Br CH₂CH₃ 4-Cl CH T I-647 CH₂Br CH₂CH₃ 4-F CH T I-648 CH₂Br CH₂CH₃ — CH T

2. Methods for producing 2-(Halogenated hydrocarbon-substituted)-5-benzyl-1-azolylmethylcyclopentanol derivatives

The method for producing Compound (I) is described below. Solvents, bases, acids and the like employed in each step in each production method described below may be those listed below unless otherwise specified.

(1) Solvents

While the solvent employed is not limited particularly unless it is involved in a reaction, it may usually be ethers such as diethyl ether, tetrahydrofuran, dioxane and the like, alcohols such as methanol, ethanol, isopropanol and the like, aromatic hydrocarbons such as benzene, toluene, xylene and the like, aliphatic hydrocarbons such as petroleum ether, hexane, methylcyclohexane and the like, amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone and the like. Otherwise, solvents may for example be water, acetonitrile, ethyl acetate, acetic anhydride, acetic acid, pyridine, dimethyl sulfoxide and the like. Two or more of these solvents may be employed in combination.

One which may also be exemplified as a solvent is a solvent composition consisting of solvents which do not form a homogenous layer with each other. In such a case, a phase transfer catalyst such as a customary employed quaternary ammonium salt or a crown ether can be added to the reaction system.

(2) Bases and Acids

To the solvent described above, a base or an acid may be added.

The base employed is not limited particularly. The base may for example be a carbonate of an alkaline metal such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate and the like; a carbonate of an alkaline earth metal such as calcium carbonate, barium carbonate and the like; a hydroxide of an alkaline metal such as sodium hydroxide, potassium hydroxide and the like; an alkaline metal such as lithium, sodium, potassium and the like; an alkoxide of an alkaline metal such as sodium methoxide, sodium ethoxide, potassium t-butoxide and the like; an alkaline metal hydride such as sodium hydride, potassium hydride, lithium hydride and the like; an organic metal compound of an alkaline metal such as n-butyl lithium and the like; an alkaline metal such as sodium, potassium, lithium and the like; an alkaline metal amide such as lithium diisopropyl amide and the like; and an organic amine such as triethylamine, pyridine, 4-dimethylaminopyridine, N,N-dimethylaniline, 1,8-diazabicyclo-7-[5.4.0]undecene and the like.

The acid employed is not limited particularly. The acid may for example be an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and the like, an organic acid such as formic acid, acetic acid, butyric acid, trifluoroacetic acid, p-toluenesulfonic acid and the like, a Lewis acid such as lithium chloride, lithium bromide, rhodium chloride, aluminum chloride, boron trifluoride and the like.

As used herein, “halogenic acid” refers to hydrofluoric acid, hydrochloric acid, hydrobromic acid and hydroiodic acid. The halogenic acid may be a gas, a liquid, or an aqueous solution. It is also possible to use as a solution formed by dissolving it in a suitable organic solvent.

(3) First Method for Producing Compound (I)

(3-1) Step 1A

Next, a production method according to the invention is described below. One embodiment of this production method comprises a step for substituting a certain functional group in a compound represented by Formula (II) shown below with a halogen atom to obtain a 2-(halogenated hydrocarbon-substituted)-5-benzyl-1-azolylmethylcyclopentanol derivative represented by Formula (Ia) shown below (Step 1A) (see Scheme (1) shown below). The compound represented by Formula (II) shown below is a compound having a leaving group on the substituent in 2-position of the cyclopentane ring. Hereinafter the compound represented by Formula (II) is referred to as “Compound (II)”, while the compound represented by Formula (Ia) is referred to as “Compound (Ia)”.

Herein, Y, m, and A are as described above. X^(a1) and X^(b1) have similar meanings as X^(a) and X^(b).

Z denotes a halogen atom. The halogen atom may for example be a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Among these, a fluorine atom, a chlorine atom and a bromine atom are preferred, with a chlorine atom being especially preferred.

Each of R^(a1) and R^(b1) independently denotes a hydrogen atom, or a C₁-C₆ alkyl group, a C₂-C₆ alkenyl group or a C₂-C₆ alkynyl group. The C₁-C₆ alkyl group, C₂-C₆ alkenyl group and C₂-C₆ alkynyl group may be substituted with X^(a1), X^(b1), L^(a), L^(b), and z.

Each of L^(a) and L^(b) denotes a halogen atom-substitutable leaving group.

n^(a1) and n^(b1) denote the numbers of X^(a1) and X^(b1) on R^(a1) and R^(b1). p^(a) and p^(b) denote the number of L^(a) and L^(b) on R^(a1) and R^(b1). “n^(a1)+p^(a)” denotes 0 or the number of hydrogen atoms substituted with X^(a1) or L^(a) or Z among the hydrogen atoms in R^(a1). “n^(b1)+p^(b)” denotes 0 or the number of hydrogen atoms substituted with X^(b1) or L^(b) or Z among the hydrogen atoms in R^(b1). “p^(a)+p^(b)” denotes an integer of 1 or more. When n^(a1) denotes 2 or more then each X^(a1) may be same or different. When n^(b1) denotes 2 or more then each X^(b1) may be same or different.

The method for substituting the leaving group with the halogen atom may for example be (a) a method for substituting a compound having a substituted sulfonyloxy group such as a p-toluenesulfonyloxy group or a methanesulfonyloxy group in a solvent with a halogenated salt, (b) a method for substituting a hydroxyl group or an alkoxy group using hydrochloric acid or hydrobromic acid, (c) a method for substituting a hydroxyl group using a halogenated phosphorus, and (d) a method for reacting a hydroxyl group with a thionyl halide.

Among substitution methods indicated as (a) to (d) described above, method indicated as (a) is preferred. Substitution method indicated as (a) is detailed below.

The reaction in the method indicated as (a) is usually conducted by mixing Compound (H) with a halogenated salt such as potassium fluoride, cesium fluoride, lithium chloride, potassium chloride, lithium bromide, magnesium bromide, and sodium iodide and the like in a solvent.

The amount of the halogenated salt employed per mole of Compound (II) is usually 0.1 to 100 moles, and preferably 0.8 to 20 moles. The reaction temperature is usually 0 to 250 degrees C., and preferably room temperature to 200 degrees C. The reaction time is usually 0.1 hour to several days, and preferably 0.2 hour to 2 days.

(3-2) Step 1B

A compound represented by Formula (IIa) employed in Step 1A (hereinafter referred to as “Compound (IIa)”) is obtained by a step for reacting a compound represented by Formula (VI) (“Compound (VI)”) with a substituted sulfonyl chloride represented by Formula (XV) (“Compound (XV)”) (“Step 1B”) (see Scheme (2) shown below). Compound (IIa) is a 5-benzyl-1-azolylmethylcyclopentanol derivative having a substituted sulfonyloxy group-substituted substituent in 2-position. Compound (VI) is a 5-benzyl-1-azolylmethylcyclopentanol derivative having a hydroxyl group-substituted substituent in 2-position.

Herein, Y, m and A are as described above. X^(a2) and X^(b2) have similar meanings as X^(a) and X^(b), respectively. L^(a1) denotes a halogen atom-substitutable substituted sulfonyloxy group.

Each of R^(a2) and R^(b2) independently denotes a hydrogen atom, or a C₁-C₆ alkyl group, a C₂-C₆ alkenyl group or a C₂-C₆ alkynyl group. The C₁-C₆ alkyl group, C₂-C₆ alkenyl group and C₂-C₆ alkynyl group may be substituted with X^(a2), X^(b2) or a hydroxyl group.

n^(a2) and n^(b2) denote the numbers of X^(a2) and X^(b2) on R^(a2) and R^(b2). p^(a1) and p^(b1) denote the number of the hydroxyl groups and L^(a1) on R^(a2) and R^(b2). “n^(a2)+p^(a1)” denotes 0 or the number of X^(a2)—, hydroxyl group- or L^(a1)-substituted hydrogen atoms among the hydrogen atoms in R^(a2). “n^(b2)+p^(b1)” p denotes 0 or the number of X^(a2)—, hydroxyl group- or L^(a1)-substituted hydrogen atoms among the hydrogen atoms in R^(b2). “p^(a1)+p^(b1)” denotes an integer of 1 or more. When n^(a2) denotes 2 or more then each X^(a2) may be same or different. When n^(b2) denotes 2 or more then each X^(b2) may be same or different.

R in Formula (XV) denotes a lower alkyl group, a phenyl group, or a naphthyl group. The lower alkyl group may for example be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a trifluoromethyl group and the like. The phenyl group and the naphthyl group may be substituted. The optionally substituted phenyl group and naphthyl group may for example be a 4-methylphenyl group, a 2-nitrophenyl group, and a 5-dimethylaminonaphthyl group. Among these, the methyl group and the 4-methylphenyl group are preferred.

The amount of Compound (XV) employed per mole of Compound (VI) is usually 0.5 to 10 moles, and preferably 0.8 to 5 moles. While the reaction may proceed without any added base, it is preferable to add a base for removing hydrogen chloride generated. In such a case, the amount of the base employed per mole of Compound (VI) is usually 0 to 5 moles or less (excluding 0), preferably 0.5 to 3 moles.

The base employed is not limited particularly. The base may for example be an alkaline metal hydride such as sodium hydride, potassium hydride, lithium hydride and the like; and an organic amine such as triethylamine, pyridine, 4-dimethylaminopyridine, N,N-dimethylaniline and the like.

The reaction temperature may appropriately be selected depending on the types of the solvent, the base and the like which are employed. The reaction temperature is preferably −50 degrees C. to 200 degrees C., and more preferably −20 degrees C. to 150 degrees C. The reaction time may appropriately be selected depending on the types of the solvent, the base and the like which are employed. The reaction time is preferably 0.1 hour to several days, and more preferably 0.5 hour to 1 day.

(3-3) Step 1C

Compound (VI) employed in Step 1B may be produced by a known method (for example, see Patent Literature 4). However, Compound (VIa) having a hydroxymethyl group and an alkyl group in 2-position is preferably produced using the synthetic method shown below.

First, a carbonyl compound represented by Formula (IX) shown below (hereinafter referred to as “Compound (IX)”) is subjected to conversion into an oxirane to obtain an oxirane derivative represented by Formula (VIII) shown below (“Compound (VIII)”). Then, the resultant Compound (VIII) is reacted with a 1,2,4-triazole or imidazole compound represented by Formula (IV) shown below (“Compound (IV)”) to obtain a compound represented by Formula (VII) shown below (“Compound (VII)”). Thereafter, the protective group of the hydroxyl group represented by G in Compound (VII) is deprotected thereby synthesizing Compound (VIa). A series of these reaction procedures (“Step 1C”) is represented by Scheme (3) shown below.

Herein, Y, m and A are as described above.

R¹ denotes a C₁-C₆ alkyl group, a C₂-C₆ alkenyl group or a C₂-C₆ alkynyl group. Specific examples of these C₁-C₆ alkyl group, C₂-C₆ alkenyl group and C₂-C₆ alkynyl group are the same as the specific examples in R^(a) and R^(b) described above, and accordingly are not specified here in detail.

G denotes a protective group, and is not limited particularly as long as Compound (VIa) can be produced from Compound (VII). The protective group can for example be an alkoxymethyl group such as a methoxymethyl group and an ethoxymethyl group, a lower alkyl group such as a t-butyl group and a methyl group as well as a substituted or unsubstituted benzyl group and the like.

M denotes a hydrogen atom or an alkaline metal.

(3-3-1) Step 1C1

A step for subjecting Compound (IX) to conversion into an oxirane to obtain Compound (VIII) (Step 1C1) in this Step 1C is described below.

First, as a first preferable synthetic method for Compound (VIII), a method involving reacting Compound (IX) with a sulfur ylide including sulfonium methylides such as dimethylsulfonium methylide and the like or sulfoxonium methylides such as dimethyl sulfoxonium methylide and the like in a solvent can be exemplified.

The sulfonium methylides and the sulfoxonium methylides employed can be produced by reacting, in a solvent, a sulfonium salt (for example, trimethylsulfonium iodide, trimethylsulfonium bromide and the like) or a sulfoxonium salt (for example, trimethylsulfoxonium iodide, trimethylsulfoxonium bromide and the like) with a base.

The amount of such a sulfonium methylide and sulfoxonium methylide per mole of Compound (IX) described above is preferably 0.5 to 5 moles, and more preferably 0.8 to 2 moles.

The solvent employed is not limited particularly. The solvent can for example be dimethyl sulfoxide, amides such as N-methylpyrrolidone, N,N-dimethylformamide and the like, ethers such as tetrahydrofuran, dioxane and the like, as well as a solvent mixture thereof.

The base employed for producing sulfonium methylides and sulfoxonium methylides is not limited particularly. The base can for example be a metal hydride such as sodium hydride and the like, an alkoxide of an alkaline metal such as sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium t-butoxide and the like.

The reaction temperature and the reaction time may appropriately be selected depending on the types of the solvent, Compound (IX), sulfonium salt or sulfoxonium salt, base and the like which are employed. The reaction temperature is preferably −100 degrees C. to 200 degrees C., and more preferably −50 degrees C. to 150 degrees C. The reaction time is preferably 0.1 hour to several days, and more preferably 0.5 hour to 2 days.

Next, as a second synthetic method for Compound (VIII), a method in which Compound (IX) is reacted with samarium iodide and diiodomethane in a solvent and subsequently treated with a base is described below.

The base is not limited particularly. The base may for example be sodium hydroxide. The samarium iodide employed can be produced by reacting a metal samarium with 1,2-diiodoethane or diiodomethane in an anhydrous solvent. The solvent employed is not limited particularly and may for example be an ether such as tetrahydrofuran and the like.

While the amount of the base per mole of Compound (IX) is not limited particularly, it is preferably 0.5 to 10 moles in usual cases, and more preferably 0.8 to 6 moles. When treating with the base, an aqueous solution of sodium hydroxide may for example be employed since no anhydrous system is required.

The reaction temperature and the reaction time may appropriately be selected depending on the types of the solvent, Compound (IX), base and the like which are employed. The reaction temperature is preferably −100 degrees C. to 150 degrees C., and more preferably −50 degrees C. to 100 degrees C. The reaction time is preferably 0.1 hour to several days, and more preferably 0.5 hour to 2 days.

(3-3-2) Step 1C2

Next, a step for reacting Compound (VIII) and Compound (IV) to obtain Compound (VII) (Step 1C2) in this Step 1C is described below.

Compound (VII) is produced by mixing Compound (VIII) with Compound (IV) in a solvent to form a carbon-nitrogen bond between the carbon atom constituting an oxirane ring in an oxirane derivative (Compound (VIII)) and the nitrogen atom in 1,2,4-triazole or imidazole.

While the solvent employed is not limited particularly, and can for example be amides such as N-methylpyrrolidone and N,N-dimethylformamide and the like.

The amount of Compound (IV) employed per mole of Compound (VIII) is preferably 0.5 to 10 moles in usual cases, and more preferably 0.8 to 5 moles. A base may be added if necessary. The amount of the base employed per mole of Compound (IV) is preferably 0 to 5 moles (excluding 0) in usual cases, and more preferably 0.5 to 2 moles.

The reaction temperature may appropriately be selected depending on the types of the solvent, the base and the like which are employed. The reaction temperature is preferably 0 degrees C. to 250 degrees C., and more preferably 10 degrees C. to 150 degrees C. The reaction time may appropriately be selected depending on the types of the solvent, the base and the like which are employed. The reaction time is preferably 0.1 hour to several days, and more preferably 0.5 hour to 2 days.

It is possible to produce Compound (VII) by producing Compound (VIII) and then reacting it stepwise with Compound (IV) as described above. Nevertheless, when the reaction for conversion into an oxirane is conducted alone in the first synthetic method described above, a by-product such as an oxetane derivative is produced, resulting in a reduced yield. In order to avoid this reduced yield, conversion into an azole may be conducted while allowing Compound (VIII) to be produced (see Scheme (4) shown below).

Herein, Y, m, A, R¹, G and M are as described above.

In such a case, Compound (IX) and Compound (IV) described above are dissolved in a polar solvent having an amide bond, or dimethyl sulfoxide or a solvent mixture of an alcohol with a polar solvent. Then, to this, a trimethylsulfonium salt or a trimethylsulfoxonium salt and a base are added intermittently to produce sulfonium methylides such as dimethylsulfonium methylide and the like or sulfoxonium methylides such as dimethyl sulfoxonium methylide and the like in the reaction system, thereby effecting the conversion into an azole while allowing Compound (VIII) to be produced.

The solvent employed here is not limited particularly. As a preferable solvent, a polar solvent having an amide bond such as N-methylpyrrolidone and N,N-dimethylformamide and the like, or dimethyl sulfoxide, or a solvent mixture of a polar solvent with an alcohol can be exemplified. The alcohol may be t-butanol.

The base employed for producing sulfonium methylides and sulfoxonium methylides are not limited particularly. The base can for example be a metal hydride such as sodium hydride and the like, an alkoxide of an alkaline metal such as sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium t-butoxide and the like. In addition, an alkaline metal salt of 1,2,4-triazole or imidazole may also be used.

The reaction temperature may appropriately be selected depending on the types of the solvent, Compound (IX), sulfonium salt or sulfoxonium salt, base and the like which are employed. The reaction temperature is preferably −100 degrees C. to 250 degrees C., and more preferably −50 degrees C. to 200 degrees C. The reaction time may appropriately be selected depending on the types of the solvent, Compound (IX), sulfonium salt or sulfoxonium salt, base and the like which are employed. The reaction time is preferably 0.1 hour to several days, more preferably 0.5 hour to 2 days.

The number of times when a trimethyl sulfonium halide or a trimethyl sulfonium halide and a base are added intermittently is not limited particularly as long as it is the number of times allowing a predetermined aim to be accomplished. A preferred number of times may usually be 2 to 20 times, with 3 to 15 times being more preferable. The total amount of a trimethylsulfonium salt or a trimethylsulfoxonium salt employed per mole of Compound (IX) is preferably 0.5 to 5 moles, more preferably 0.8 to 2 moles.

The amount of Compound (IV) employed per mole of Compound (IX) is preferably 0.5 to 10 moles in usual cases, and more preferably 0.8 to 5 moles. It is preferable to use Compound (IV) in which M is an alkaline metal salt.

For details of the steps for conducting the conversion into an azole while allowing the oxirane derivative to be produced in the production of the azolylmethylcycloalkanol derivative, see Patent Literature 5.

(3-3-3) Step 1C3

Next, a step for deprotecting the protective group of Compound (VII) to obtain Compound (VIa) (Step 1C3) in this Step 1C is described below.

Although a preferred condition differs depending on the type of the protective group, in the cases, for example, of using an alkoxymethyl group such as a methoxymethyl group or an ethoxyethyl group or a lower alkyl group such as a t-butyl group or a methyl group, the deprotection is conducted preferably in a solvent under an acidic condition involving hydrogen chloride or sulfuric acid and the like.

The acid employed here is preferably a halogenated hydrogen such as hydrogen chloride or an inorganic acid such as sulfuric acid. While the amount employed is not limited particularly, the amount of the acid employed per mole of Compound (VII) is usually 0.5 to 100 moles, and preferably 0.8 to 20 moles.

The reaction temperature is preferably 0 degrees C. to 200 degrees C. in usual cases, and more preferably room temperature to 100 degrees C. The reaction time is preferably 0.1 hour to several days in usual cases, more preferably 0.5 hour to 2 days.

(3-4) Step 1D

Compound (XII) employed in Step 1C can preferably be synthesized by the method shown below.

Thus, a keto ester compound represented by Formula (XII) shown below (hereinafter referred to as “Compound (XII)”) is hydroxymethylated to obtain a compound represented by Formula (XI) shown below (“Compound (XI)”). Then, a protective group such as a methoxymethyl group or a t-butyl group and the like is introduced into the hydroxyl group in Compound (XI) to effect derivatization into a compound represented by Formula (X) shown below (“Compound (X)”). Thereafter, Compound (X) is hydrolyzed/decarbonated to obtain a carbonyl compound represented by Formula (XI) shown below (“Compound (XI)”). A series of these reaction procedures (“Step 1D”) is represented by Scheme (5) shown below.

Herein, Y, m, R¹ and G are as described above.

R² denotes a C1-C4 alkyl group. The specific examples of the alkyl groups in R² are the same as the specific examples in R^(a) and R^(b) described above, and accordingly are not specified here in detail.

(3-4-1) Step 1D1

In this Step 1D, in the step for obtaining Compound (XI) by hydroxymethylating Compound (XII), a method involving a reaction with formaldehyde in the presence of a base in a solvent may be employed.

The amount of formaldehyde employed per mole of Compound (XII) is usually 0.5 to 20 moles, and preferably 0.8 to 10 moles.

The base can for example be, but not limited to, a carbonate of an alkaline metal such as sodium carbonate, potassium carbonate and the like as well as a hydroxide of an alkaline metal such as sodium hydroxide and the like. The amount of the base employed per mole of Compound (XII) is usually 0.1 to 10 moles, and preferably 0.2 to 5 moles.

The reaction temperature is preferably 0 degrees C. to 250 degrees C. in usual cases, and more preferably 0 to 100 degrees C. The reaction time is preferably 0.1 hour to several days in usual cases, and more preferably 0.5 hour to 2 days.

Compound (XII) employed here may be produced by a known method (for example, the method disclosed in Patent Literature 1).

(3-4-2) Step 1D2

Next, a step for introducing a protective group into the hydroxyl group in Compound (XI) to obtain Compound (X) (Step 1D2) in this Step 1D is described below.

While the protective group for protecting the hydroxyl group is not limited particularly, those employed preferably are an alkoxymethyl group such as a methoxymethyl group and an ethoxymethyl group, and a lower alkyl group such as a t-butyl group and the like. Introduction of these protective group is conducted preferably by (a) an acetal exchange of the hydroxyl group in Compound (XII) using a formaldehyde dialkylacetal in the case of introduction of an alkoxymethyl group. (b) Addition of the hydroxyl group in Compound (XII) using isobutene is utilized preferably in the case of introduction of a t-butyl group.

First, the case (a) mentioned above is described below.

As an acid, an inorganic acid such as hydrochloric acid, phosphoric acid (including a compound allowing an acidic group to be generated by addition of an alcohol or water, such as diphosphorus pentoxide) and sulfuric acid, and an organic acid such as p-toluenesulfonic acid and the like are employed. In the presence of such an acid, a formaldehyde dialkylacetal is employed preferably in a solvent or in a solvent-free system. It is further preferred to add a compound allowing any generated alcohol to be removed, such as diphosphorus pentoxide.

The amount of the formaldehyde dialkylacetal employed per mole of Compound (XI) is usually 0.5 to 50 moles, and preferably 0.8 to 10 moles. The amount of the acid employed per mole of Compound (XI) is usually 0.01 to 10 moles, and preferably 0.05 to 5 moles.

The reaction temperature is preferably 0 degrees C. to 250 degrees C. in usual cases, and more preferably 0 degrees C. to 150 degrees C. The reaction time is preferably 0.1 hour to several days in usual cases, and more preferably 0.5 hour to 2 days.

In the case (b) mentioned above, it is preferred to conduct a reaction with isobutene in a solvent in the presence of an inorganic acid such as hydrochloric acid, phosphoric acid and sulfuric acid and the like, or an organic acid such as p-toluenesulfonic acid and trifluoroacetic acid and the like.

The amount of isobutene employed per mole of Compound (XI) is usually 0.5 to 100 moles, and preferably 0.8 to 20 moles. The amount of the acid employed per mole of Compound (XI) is usually 0.01 to 10 moles, and preferably 0.05 to 5 moles.

The reaction temperature is preferably 0 degrees C. to 200 degrees C. in usual cases, and more preferably 0 degrees C. to 100 degrees C. The reaction time is preferably 0.1 hour to several days in usual cases, and more preferably 0.5 hour to 2 days.

(3-4-3) Step 1D3

Next, a step for hydrolyzing/decarbonating Compound (X) to obtain Compound (IX) (Step 1D3) in this Step 1D is described below.

This reaction is conducted preferably in the presence of a base in a solvent. The base employed usually includes an alkaline metal base such as sodium hydroxide, potassium hydroxide and the like. The amount of base employed per mole of Compound (X) is usually 0.1 to 50 moles, and preferably 0.2 to 20 moles.

The solvent may usually be water, as well as water combined with an alcohol and the like, a solvent mixture consisting of solvents which do not form a homogenous layer with each other (such as water-toluene) (in such a case it may sometimes be preferable to use a phase transfer catalyst, such as a customary quaternary ammonium salt, in the reaction system).

The reaction temperature is preferably 0 degrees C. to reflux temperature in usual cases, and more preferably room temperature to reflux temperature. The reaction time is preferably 0.1 hour to several days in usual cases, and more preferably 0.5 hour to 24 hours.

(4) Second Method for Producing Compound (I)

(4-1) Step 2A

Another embodiment of the production method according to the invention is described. This embodiment comprises a step for subjecting a carbonyl compound represented by Formula (V) shown below to conversion into an oxirane thereby obtaining an oxirane derivative represented by Formula (III) shown below which is then reacted with a compound represented by Formula (IV) shown below to obtain Compound (I) (Step 2A) (see Scheme (6) shown below). Hereinafter, the carbonyl compound represented by Formula (V) is referred to as “Compound (V)”, while the oxirane derivative represented by Formula (III) is referred to as “Compound (III)”.

Herein, R^(a), R^(b), X^(a), X^(b), n^(a), n^(b), Y, m, A and M are as described above.

(4-1-1) Step 2A1

First, a step for converting Compound (V) into an oxirane to obtain Compound (III) (Step 2A1) is described below.

As a first preferable synthetic method for Compound (III), a method involving reacting Compound (V) with a sulfur ylide including sulfonium methylides such as dimethylsulfonium methylide and the like or sulfoxonium methylides such as dimethyl sulfoxonium methylide and the like in a solvent can be exemplified.

The sulfonium methylides or the sulfoxonium methylides can be produced by reacting, in a solvent, a sulfonium salt (for example, trimethylsulfonium iodide, trimethylsulfonium bromide and the like) or a sulfoxonium salt (for example, trimethylsulfoxonium iodide, trimethylsulfoxonium bromide and the like) with a base. While the base is not limited particularly, those employed preferably include a metal hydride such as sodium hydride and the like, an alkoxide of an alkaline metal such as sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium t-butoxide and the like.

The amount of such a sulfonium methylide and sulfoxonium methylide per mole of Compound (V) is 0.5 to 5 moles, and preferably 0.8 to 2 moles.

While the solvent employed is not limited particularly, it may for example be dimethyl sulfoxide, amides such as N-methylpyrrolidone and N,N-dimethylformamide and the like, ethers such as tetrahydrofuran, dioxane and the like, as well as a solvent mixture thereof.

While the reaction temperature may appropriately be selected depending on the types of the solvent, Compound (V), sulfonium salt or sulfoxonium salt, base and the like which are employed, it is preferably −100 degrees C. to 200 degrees C., and more preferably −50 degrees C. to 150 degrees C. While the reaction time may appropriately be selected depending on the types of the solvent, Compound (V), sulfonium salt or sulfoxonium salt, base and the like which are employed, it is preferably 0.1 hour to several days, and more preferably 0.5 hour to 2 days.

As a second preferable synthetic method for Compound (III), a method involving reacting Compound (V) with samarium iodide and diiodomethane in a solvent and then treating it with a base can be exemplified. The base employed is not limited particularly and may for example be sodium hydroxide.

The amount of samarium iodide per mole of Compound (V) is usually 0.5 to 10 moles, and preferably 1 to 6 moles. The amount of diiodomethane per mole of Compound (V) is usually 0.5 to 10 moles, and preferably 0.8 to 5 moles. The samarium iodide can be produced by reacting a metal samarium with 1,2-diiodoethane or diiodomethane in an anhydrous solvent.

While the amount of the base per mole of Compound (V) is not limited particularly, it is preferably 0.5 to 10 moles in usual cases, and more preferably 0.8 to 6 moles. When treating with the base, an aqueous solution of sodium hydroxide may for example be employed since no anhydrous system is required.

The reaction temperature and the reaction time may appropriately be selected depending on the types of the solvent, Compound (V), base and the like which are employed. The reaction temperature is preferably −100 degrees C. to 150 degrees C., and more preferably −50 degrees C. to 100 degrees C. The reaction time is preferably 0.1 hour to several days, and more preferably 0.5 hour to 2 days.

(4-2-2) Step 2A2

Next, a step for obtaining Compound (I) from Compound (III) and Compound (IV) (Step 2A2) is described below.

Compound (I) is produced by mixing Compound (III) with Compound (IV) in a solvent to form a carbon-nitrogen bond between the carbon atom constituting an oxirane ring in an oxirane derivative and the nitrogen atom in 1,2,4-triazole or imidazole.

While the solvent employed is not limited particularly, it can for example be amides such as N-methylpyrrolidone and N,N-dimethylformamide and the like.

The amount of Compound (IV) employed per mole of Compound (III) is preferably 0.5 to 10 moles in usual cases, and more preferably 0.8 to 5 moles. A base may be added if necessary. The amount of the base employed per mole of Compound (IV) is preferably 0 to 5 moles (excluding 0) in usual cases, and more preferably 0.5 to 2 moles.

The reaction temperature may appropriately be selected depending on the types of the solvent, the base and the like which are employed. The reaction temperature is preferably 0 degrees C. to 250 degrees C., and more preferably 10 degrees C. to 150 degrees C. The reaction time may appropriately be selected depending on the types of the solvent, the base and the like which are employed. The reaction time is preferably 0.1 hour to several days, and more preferably 0.5 hour to 2 days.

(4-2) Step 2B

While for Compound (V) employed in Step 2A it is possible to use a compound which can be synthesized by a conventional technology, Compound (Va) is preferably produced by the following synthetic method.

First, in the presence of a base, Compound (XII) is reacted with a halogenated compound represented by Formula (XIV) shown below (hereinafter referred to as “Compound (XIV)”) to obtain a keto ester compound represented by Formula (XIII) (refereed to as “Compound (XIII)”). Subsequently, Compound (XIII) thus obtained is hydrolyzed/decarbonated to obtain Compound (Va). A series of these reaction procedures (“Step 2B”) is represented by Scheme (7) shown below.

Herein, R¹, R², Y and m are as described above. R^(a1), X^(a1) and n^(a1) have similar meanings as R^(a), X^(a) and n^(a), respectively.

First, a step for reacting Compound (XII) in the presence of a base with Compound (XIX) to obtain Compound (XIII) (Step 2B1) is described below.

This reaction is conducted preferably in a solvent. The base is not limited particularly, and includes alkaline metal hydrides such as sodium hydride and the like, and alkaline metal carbonates such as sodium carbonate, potassium carbonate and the like. The amount of the base per mole of Compound (XII) is preferably 0.5 to 5 moles, and more preferably 0.8 to 2 moles.

The amount of Compound (XIV) per mole of Compound (XII) is preferably 0.5 to 10 moles, and more preferably 0.8 to 5 moles.

While the reaction temperature may appropriately be selected depending on the types of the solvent, Compound (XII), Compound (XIV), base and the like which are employed, it is preferably 0 degrees C. to 250 degrees C., and more preferably room temperature to 150 degrees C. While the reaction time may appropriately be selected depending on the types of the solvent, Compound (XII), Compound (XIV), base and the like which are employed, it is preferably 0.1 hour to several days, and more preferably 0.5 hour to 24 hours.

(4-2-2) Step 2B2

Next, a step for hydrolyzing/decarbonating Compound (XIII) (Step 2B2) is described below.

This reaction can be conducted in a solvent under both of a basic condition and an acidic condition.

When conducting hydrolysis under the basic condition, the base is usually an alkaline metal base such as sodium hydroxide, potassium hydroxide and the like. The solvent is usually water, as well as water combined with alcohols.

When conducting hydrolysis under the acidic condition, the acid catalyst is an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid and the like. The solvent is usually water, or water combined with an organic acid such as acetic acid.

The reaction temperature is preferably 0 degrees C. to reflux temperature in usual cases, and more preferably room temperature to reflux temperature. The reaction time is usually 0.1 hour to several days, and preferably 0.5 hour to 24 hours.

(5) Third Method for Producing Compound (I)

(5-1) Step 3A

Another embodiment of the production method according to the invention is described. This embodiment comprises a step for reacting a compound represented by Formula (VIb) shown below (“Compound VIb”) with a substituted sulfonyl chloride group represented by Formula (XV) shown below (“Compound (XV)”) to obtain an oxetane compound represented by Formula (XVI) shown below (“Compound (XVI)”). Also included is a step for subjecting Compound (XVI) to ring opening using any halogenic acid to obtain Compound (Ib) (Step 3A; see Scheme (8) shown below). Compound (VIb) is a 5-benzyl-1-azolylmethylcyclopentanol derivative having a hydroxyl group-substituted substituent in 2-position, and corresponds to Compound (VI) wherein R^(a1)═R^(a), X^(a1)═X^(a), n^(a1)=n^(a), p^(a1)=0, R^(b2)=methyl group, n^(b2)=0, and p^(b1)=1.

Herein, R^(a), X², n^(a), R, Y, m and X^(b) are as described above.

(5-1-1) Step 3A1

First, a step for subjecting Compound (VIb) to ring closing to obtain an oxetane compound (XVI) (Step 3A1) is described below.

As a preferable synthetic method for Compound (XVI), a method for reacting Compound (VIb) in the presence of a sulfonyl chloride and an excessive amount of base in a solvent can be exemplified.

The sulfonyl chloride may for example be p-toluenesulfonyl chloride and methanesulfonyl chloride and the like. Among these, p-toluenesulfonyl chloride is employed preferably. While the base is not limited particularly, those employed preferably include a metal hydride such as sodium hydride and the like, an alkoxide of an alkaline metal such as sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium t-butoxide and the like.

The amount of the sulfonyl chloride per mole of Compound (VIb) is preferably 0.5 to 5 moles, and more preferably 0.8 to 2 moles. The amount of the base is preferably 1.5 to 5 moles, and more preferably 1.8 to 3 moles.

While the solvent is not limited particularly, it includes amides such as N-methylpyrrolidone and N,N-dimethylformamide and the like, ethers such as tetrahydrofuran and dioxane and the like, or dimethyl sulfoxide as well as solvent mixtures thereof.

While the reaction temperature may appropriately be selected depending on the types of the solvent, Compound (VIb), sulfonyl chloride, base and the like which are employed, it is preferably −100 degrees C. to 200 degrees C., and more preferably −50 degrees C. to 150 degrees C. While the reaction time may appropriately be selected depending on the types of the solvent, Compound (VIb), sulfonyl chloride, base and the like which are employed, it is preferably 0.1 hour to several days, and more preferably 0.5 hour to 2 days.

(5-1-2) Step 3A2

Next, a step for obtaining Compound (Ib) from Compound (XVI) (Step 3A2) is described below.

Compound (Ib) can be produced preferably by mixing Compound (XVI) with Compound H—X^(b) in a solvent to effect ring opening of the oxetane ring possessed by Compound (XVI) thereby producing a halogenated methyl group and a tertiary hydroxyl group.

H—X^(b) denotes a halogenic acid, such as hydrogen chloride, hydrogen bromide, hydrogen iodide and the like. The halogenic acid may be introduced also as a gas, and it may be added as being dissolved in an organic solvent solution. It is possible to add a halogenic acid salt and an acid irrelevant to the halogenic acid salt (such as toluenesulfonic acid, methanesulfonic acid and the like) thereby obtaining Compound (Ib) from Compound (XVI).

While the solvent employed is not limited particularly, it may for example be amides such as N-methylpyrrolidone and N,N-dimethylformamide and the like, alcohols such as methanol and ethanol, and ethers such as tetrahydrofuran, dioxane and the like.

The amount of Compound H—X^(b) employed per mole of Compound (XVI) is usually 0.5 to 50 moles, and preferably 1 to 20 moles.

While the reaction temperature may appropriately be selected depending on the types of the solvent, base and the like which are employed, it is preferably −20 degrees C. to 250 degrees C., and more preferably −10 degrees C. to 150 degrees C. While the reaction time may appropriately be selected depending on the types of the solvent, base and the like which are employed, it is preferably 0.1 hour to several days, and more preferably 0.5 hour to 2 days.

Compound (VIb) employed in Step 3A1 can be synthesized by the method similar to Step 1C and Step 1D described in the first production method. The entire steps of the third production method involving the step for synthesizing Compound (VIb) is indicated in Scheme (9) shown below.

(6) Fourth Method for Producing Compound (I)

(6-1) Step 4A

Another embodiment of the production method according to the invention is described. This embodiment comprises a step for subjecting a bishydroxymethyl compound represented by Formula (XIX) shown below (“Compound (XIX)”, which is the case of Compound (VI) wherein (R^(a2))X^(a2)n^(a2)(OH)P^(a1)═CH₂OH, (R^(b2))X^(b2)n^(b2) (OH)p^(b1)=CH₂OH) to ring closing into an oxetane compound while subjecting another side chain to sulfonylation to obtain an oxetane sulfonyl ester derivative represented by Formula (XX) shown below (“Compound (XX)”). Also included is a step for reducing the sulfonyl side chain of Compound (XX) into an alkyl group to obtain a 1-alkyl-6-oxabicyclo[3,2,1]heptane derivative represented by Formula (XXI) shown below (“Compound (XXI)”). Also included is a step for subjecting the oxetane in Compound (XXI) to ring opening using an acid to yield a halogenated methyl group thereby obtaining Compound (Id) (Step 4A; see Scheme (10) shown below). Compound (XIX) corresponds to Compound (VI) wherein (R^(a2))X^(a2)n^(a2) (OH)p^(a1)=CH₂ OH, (R^(b2))X^(b2)n^(b2) (OH)p^(b1)=CH₂OH.

Herein, Y, m, A and X^(b), are as described above.

R³ denotes a lower alkyl group, a phenyl group or a naphthyl group. The lower alkyl group may for example be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, and a trifluoromethyl group. The phenyl group and the naphthyl group may be substituted. The phenyl group and the naphthyl group which may be substituted may for example be a 4-methylphenyl group, a 2-nitrophenyl group and a 5-dimethylaminonaphthyl group. Among these, the methyl group or the 4-methylphenyl group is employed preferably.

(6-1-1) Step 4A1

First, a step for converting Compound (XIX) into an oxetane while sulfonylating it to obtain Compound (XX) (Step 4A1) is described below.

As a preferable synthetic method for Compound (XX), a method involving reacting Compound (XIX) in the presence of 2 equivalents or more of a sulfonyl chloride and an excessive amount of a base in a solvent can be exemplified

The sulfonyl chloride may for example be p-toluenesulfonyl chloride, methanesulfonyl chloride and the like. Among these, p-toluenesulfonyl chloride is employed preferably. While the base is not limited particularly, those employed preferably include a metal hydride such as sodium hydride and the like, and an alkoxide of an alkaline metal such as sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium t-butoxide and the like.

The amount of the sulfonyl chloride per mole of Compound (XIX) is preferably 1.8 to 10 moles, and more preferably 2 to 5 moles. The amount of the base is preferably 2.5 to 10 moles, and more preferably 2.8 to 6 moles.

While the solvent is not limited particularly, it includes amides such as N-methylpyrrolidone and N,N-dimethylformamide and the like, ethers such as tetrahydrofuran and dioxane and the like, or dimethyl sulfoxide as well as solvent mixtures thereof.

While the reaction temperature may appropriately be selected depending on the types of the solvent, Compound (XIX), sulfonyl chloride, base and the like which are employed, it is preferably −100 degrees C. to 200 degrees C., and more preferably −50 degrees C. to 150 degrees C. While the reaction time may appropriately be selected depending on the types of the solvent, Compound (XIX), sulfonyl chloride, base and the like which are employed, it is preferably 0.1 hour to several days, and more preferably 0.5 hour to 2 days.

(6-1-2) Step 4A2

Next, a step for obtaining Compound (XXI) from Compound (XX) (Step 4A2) is described below.

In a suitable solvent, a variety of general reducing condition can be employed to reduce the sulfonyloxy group in Compound (XX) thereby obtaining Compound (XXI).

The reducing agent can for example be a metal, a hydride type reducing agent, a hydrogen/catalytic hydrogenation catalyst and the like. For example, the metal includes an iron powder, a zinc powder, a combination of a zinc powder and NaI and the like. The hydride type reducing agent includes sodium borohydride, lithium borohydride, lithium aluminum hydride and the like. The catalytic hydrogenation catalyst includes a palladium/carbon, a palladium hydroxide/carbon, a platinum/carbon, a Raney nickel and the like. Among these, the metal powder is employed preferably, with a combination of the zinc powder and NaI being more preferred.

The solvent is not limited particularly, and may appropriately be selected depending on the type of the reducing agent. The solvent may be an ether based solvent such as tetrahydrofuran, diethyl ether and the like, an alcohol based solvent such as methanol, ethanol and the like, or a protic solvent having a high polar ratio such as dimethyl sulfoxide, dimethyl formamide and the like.

The amount of the reducing agent employed per mole of Compound (XX) is usually 0.5 to 50 moles, and preferably 1 to 20 moles.

While the reaction temperature may appropriately be selected depending on the types of the solvent, base and the like which are employed, it is preferably −20 degrees C. to 250 degrees C., and more preferably −10 degrees C. to 150 degrees C. While the reaction time may appropriately be selected depending on the types of the solvent, base and the like which are employed, it is preferably 0.1 hour to several days, and more preferably 0.5 hour to 3 days.

(6-1-3) Step 4A3

Next, a step for obtaining Compound (Id) from Compound (XXI) (Step 4A3) is described below.

In this step, Compound (Id) can be produced by mixing Compound (XXI) with Compound H—X^(b) in a solvent to effect ring opening of the oxetane ring possessed by Compound (XXI) thereby producing a halogenated methyl group and a tertiary hydroxyl group.

H—X^(b) denotes a halogenic acid, such as hydrogen chloride, hydrogen bromide, hydrogen iodide and the like. The halogenic acid may be introduced also as a gas, and it may be added as being dissolved in an organic solvent solution. It is possible to add an acid irrelevant to the halogenic acid salt (such as toluenesulfonic acid, methanesulfonic acid and the like) thereby obtaining Compound (Id) from Compound (XXI).

While the solvent employed is not limited particularly, it may for example be amides such as N-methylpyrrolidone and N,N-dimethylformamide and the like, alcohols such as methanol and ethanol, and ethers such as tetrahydrofuran, dioxane and the like.

The amount of Compound H—X^(b) employed per mole of Compound (XXI) is usually 0.5 to 50 moles, and preferably 1 to 20 moles.

While the reaction temperature may appropriately be selected depending on the types of the solvent, H—X^(b) and the like which are employed, it is preferably −20 degrees C. to 250 degrees C., and more preferably −10 degrees C. to 150 degrees C. While the reaction time may appropriately be selected depending on the types of the solvent, base and the like which are employed, it is preferably 0.1 hour to several days, and more preferably 0.5 hour to 2 days.

(6-2) Step 4B

Compound (XIX) employed in Step 4A may be produced preferably by the following method.

First, a carbonyl compound represented by Formula (XXII) shown below (hereinafter referred to as “Compound (XXII)”) is subjected to conversion into an oxirane to obtain an oxirane derivative represented by Formula (XXIII) shown below (“Compound (XXIII)”). Then, the resultant Compound (XXIII) is reacted with a 1,2,4-triazole or imidazole compound represented by Formula (IV) shown below (“Compound (IV)”) to obtain a compound represented by Formula (XXIV) shown below (“Compound (XXIV)”). Thereafter, the protective group of the hydroxyl group represented by G in Compound (XXIV) is deprotected thereby synthesizing Compound (XIX). A series of these reaction procedures (“Step 4B”) is represented by Scheme (11) shown below.

Herein, Y, m, A and M are as described above.

G² denotes a protective group, and is not limited particularly as long as Compound (XIX) can be produced from Compound (XXIV). The protective group can for example be an alkoxymethyl group such as a methoxymethyl group and an ethoxymethyl group, a lower alkyl group such as a t-butyl group and a methyl group as well as a substituted or unsubstituted benzyl group and the like. Two G²s may also be taken together to form a ring, in which case the protective group may for example be methylene acetal, isopropylidene ketal and the like.

(6-2-1) Step 4B1

A step for subjecting Compound (XXII) to conversion into an oxirane to obtain Compound (XXIII) (Step 4B1) in this Step 4B is described below.

As a first synthetic method for Compound (XXIII), a method involving reacting Compound (XXII) with a sulfur ylide in a solvent can be exemplified. The sulfur ylide may for example be sulfonium methylides such as dimethylsulfonium methylide and the like or sulfoxonium methylides such as dimethyl sulfoxonium methylide and the like.

The sulfonium methylides or the sulfoxonium methylides employed can be produced by reacting, in a solvent, a sulfonium salt (for example, trimethylsulfonium iodide, trimethylsulfonium bromide and the like) or a sulfoxonium salt (for example, trimethylsulfoxonium iodide, trimethylsulfoxonium bromide and the like) with a base.

The amount of such a sulfonium methylide or sulfoxonium methylide employed per mole of Compound (XXII) described above is preferably 0.5 to 5 moles, and more preferably 0.8 to 2 moles.

While the solvent employed is not limited particularly, it can for example be amides such as N-methylpyrrolidone and N,N-dimethylformamide and the like, ethers such as tetrahydrofuran, dioxane and the like, as well as a solvent mixture thereof.

The base employed for producing sulfonium methylides and sulfoxonium methylides are not limited particularly. The base can for example be a metal hydride such as sodium hydride and the like, and an alkoxide of an alkaline metal such as sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium t-butoxide and the like.

The reaction temperature and the reaction time are appropriately selected depending on the types of the solvent, Compound (XXII), sulfonium salt or sulfoxonium salt, base and the like which are employed. The reaction temperature is preferably −100 degrees C. to 200 degrees C., and more preferably −50 degrees C. to 150 degrees C. The reaction time is preferably 0.1 hour to several days, and more preferably 0.5 hour to 2 days.

Next, another synthetic method (a second synthetic method) for Compound (XXIII) is described. Specifically, Compound (XXIII) can be produced by reacting Compound (XXII) with samarium iodide and diiodomethane in a solvent, and then treating the reactant with a base.

While the base is not limited particularly, and may for example be sodium hydroxide. The samarium iodide employed can be produced by reacting a metal samarium with 1,2-diiodoethane or diiodomethane in an anhydrous solvent. The solvent employed is not limited particularly and may for example be an ether such as tetrahydrofuran and the like.

While the amount of the base per mole of Compound (XXII) is not limited particularly, it is preferably 0.5 to 10 moles in usual cases, and more preferably 0.8 to 6 moles. When treating with the base, an aqueous solution of sodium hydroxide may for example be employed since no anhydrous system is required.

The reaction temperature and the reaction time may appropriately be selected depending on the types of the solvent, Compound (XXII), base and the like which are employed. The reaction temperature is preferably −100 degrees C. to 150 degrees C., and more preferably −50 degrees C. to 100 degrees C. The reaction time is preferably 0.1 hour to several days, and more preferably 0.5 hour to 2 days.

(6-2-2) Step 4B2

Next, a step for reacting Compound (XXIII) and Compound (IV) to obtain Compound (XXIV) (Step 4B2) in this Step 4B is described below.

Compound (XXIV) is produced by mixing Compound (XXIII) with Compound (IV) in a solvent to form a carbon-nitrogen bond between the carbon atom constituting an oxirane ring in an oxirane derivative (Compound (XXIII)) and the nitrogen atom in 1,2,4-triazole or imidazole (Compound (IV)).

While the solvent employed is not limited particularly, and can for example be amides such as N-methylpyrrolidone and N,N-dimethylformamide and the like.

The amount of Compound (IV) employed per mole of Compound (XXIII) is preferably 0.5 to 10 moles in usual cases, and more preferably 0.8 to 5 moles. A base may be added if necessary. The amount of the base employed per mole of Compound (IV) is preferably 0 to 5 moles (excluding 0) in usual cases, and more preferably 0.5 to 2 moles.

While the reaction temperature may appropriately be selected depending on the types of the solvent, the base and the like which are employed, it is preferably 0 degrees C. to 250 degrees C., and more preferably 10 degrees C. to 150 degrees C. While the reaction time may also appropriately be selected depending on the types of the solvent, the base and the like which are employed, it is preferably 0.1 hour to several days, and more preferably 0.5 hour to 2 days.

It is possible to produce Compound (XXIV) by producing Compound (XXII) and then reacting it stepwise with Compound (IV) as described above. Nevertheless, in the first synthetic method described above, when the reaction for conversion into an oxirane is conducted alone, a by-product (such as an oxetane derivative) is produced, resulting in a reduced yield. In order to avoid this reduced yield, conversion into an azole may be conducted while allowing Compound (XXIII) to be produced (see Scheme (12) shown below).

Herein, Y, m, A, G² and M are as described above.

In such a case, Compound (XXII) and Compound (IV) are dissolved in a polar solvent having an amide bond, or dimethyl sulfoxide, or a solvent mixture of a polar solvent with an alcohol. Then, to this, a trimethylsulfonium salt or a trimethylsulfoxonium salt and a base are added intermittently to produce sulfonium methylides such as dimethylsulfonium methylide and the like or sulfoxonium methylides such as dimethyl sulfoxonium methylide and the like in the reaction system, thereby effecting the conversion into an azole while allowing Compound (XXIII) to be produced.

The solvent employed here is not limited particularly. The solvent may for example be a polar solvent having an amide bond such as N-methylpyrrolidone and N,N-dimethylformamide and the like, or dimethyl sulfoxide. The alcohol in the solvent mixture may for example be t-butanol.

The base employed for producing sulfonium methylides or sulfoxonium methylides is not limited particularly. The base can for example be a metal hydride such as sodium hydride and the like, an alkoxide of an alkaline metal such as sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium t-butoxide and the like. It is possible to use an alkaline metal salt of 1,2,4-triazole or imidazole.

The reaction temperature may appropriately be selected depending on the types of the solvent, Compound (XXII), sulfonium salt or sulfoxonium salt, base and the like which are employed. The reaction temperature is preferably −100 degrees C. to 250 degrees C., and more preferably −50 degrees C. to 200 degrees C. The reaction time may appropriately be selected depending on the types of the solvent, Compound (XXII), sulfonium salt or sulfoxonium salt, base and the like which are employed. The reaction time is preferably 0.1 hour to several days, and more preferably 0.5 hour to 2 days.

The number of times when a trimethyl sulfonium halide or a trimethyl sulfonium halide and a base are added intermittently is not limited particularly as long as it is the number of times allowing a predetermined aim to be accomplished. A preferred number of times is 2 to 20 times, with 3 to 15 times being more preferable. The total amount of a trimethylsulfonium salt or a trimethylsulfoxonium salt employed per mole of Compound (XXII) is preferably 0.5 to 5 moles, and more preferably 0.8 to 2 moles.

The amount of Compound (IV) employed per mole of Compound (XXII) is preferably 0.5 to 10 moles in usual cases, and more preferably 0.8 to 5 moles. It is preferable to use Compound (IV) in which M is an alkaline metal salt.

See Patent Literature 4 for the details of the steps for conducting conversion into an azole while allowing an oxirane derivative to be produced in the production of a certain azolylmethylcycloalkanol derivative.

(6-2-3) Step 4B3

Next, a step for deprotecting the protective group of Compound (XXIV) to obtain Compound (XIX) (Step 4B3) in this Step 4B is described below.

A preferred condition of the deprotection differs depending on the type of the protective group. Nevertheless, in the cases of using an alkoxymethyl group such as a methoxymethyl group, an ethoxyethyl group and the like, or a lower alkyl group such as a t-butyl group, a methyl group and the like, or a cyclic acetal or ketal protective group such as methylene acetal, isopropylidene ketal and the like, the deprotection is conducted preferably in a solvent under an acidic condition involving hydrogen chloride or sulfuric acid and the like.

The acid employed preferably in the deprotection may be a halogenated hydrogen such as hydrogen chloride or an inorganic acid such as sulfuric acid. While the amount employed is not limited particularly, the amount of the acid employed per mole of Compound (XXIV) is usually 0.5 to 100 moles, and preferably 0.8 to 20 moles.

The reaction temperature is preferably 0 degrees C. to 200 degrees C. in usual cases, and more preferably room temperature to 100 degrees C. The reaction time is preferably 0.1 hour to several days in usual cases, and more preferably 0.5 hour to 2 days.

(6-3) Step 4C

Compound (XXII) employed in Step 4B can preferably be synthesized by the method shown below.

Thus, a keto ester compound represented by Formula (XXV) shown below (hereinafter referred to as “Compound (XXV)”) is hydroxymethylated to obtain a compound represented by Formula (XXVI) shown below (“Compound (XXVI)”). Then, a protective group such as a methoxymethyl group, a t-butyl group and the like is introduced into the hydroxyl group in Compound (XXVI) to effect derivatization into a compound represented by Formula (XXVII) shown below (“Compound (XXVII)”). Thereafter, Compound (XXVII) is hydrolyzed/decarbonated to obtain a carbonyl compound represented by Formula (XXII) shown below (“Compound (XXII)”). A series of these reaction procedures (Step 4C) is represented by Scheme (13) shown below.

Herein, Y, m, R² and G² are as described above.

(6-3-1) Step 4C1

A step for bishydroxymethylating Compound (XXV) to obtain Compound (XXVI) (Step 4C1) in this Step 4C is described below. Compound (XXVI) can be produced by reacting Compound (XXV) with formaldehyde in the presence of a base in a solvent

The amount of formaldehyde employed per mole of Compound (XXV) is preferably 0.5 to 20 moles in usual cases, and more preferably 0.8 to 10 moles.

The base can for example be, but not limited to, a carbonate of an alkaline metal such as sodium carbonate, potassium carbonate and the like as well as a hydroxide of an alkaline metal such as sodium hydroxide and the like. The amount of the base employed per mole of Compound (XXV) is preferably 0.1 to 10 moles in usual cases, and more preferably 0.2 to 5 moles.

The reaction temperature is preferably 0 degrees C. to 250 degrees C. in usual cases, and more preferably 0 degrees C. to 100 degrees C. The reaction time is preferably 0.1 hour to several days in usual cases, and more preferably 0.5 hour to 2 days.

Compound (XII) employed may be a compound produced by a known method (for example, the method disclosed in Patent Literature 1).

(6-3-2) Step 4C2

Next, a step for introducing a protective group into the hydroxyl group in Compound (XXVI) to obtain Compound (XXVII) (Step 4C2) in this Step 4C is described below.

The protective group for protecting the hydroxyl group is not limited particularly. The protective group is preferably an alkoxymethyl group such as a methoxymethyl group, an ethoxymethyl group and the like, or a lower alkyl group such as a t-butyl group and the like. Introduction of these protective groups is conducted under an acidic condition. Nevertheless, a method involving (a) an acetal exchange of the hydroxyl group in Compound (XXVI) using a formaldehyde dialkylacetal in the case of introduction of an alkoxymethyl group is preferred. (b) Introduction of the protective group to the hydroxyl group in Compound (XXVI) using isobutene is utilized preferably in the case of introduction of a t-butyl group. (c) A suitable aldehyde or ketone is employed preferably under an acidic catalyst when protecting 2 hydroxyl groups with acetal and ketal at the same time.

First, the case where the protective group is an alkoxymethyl group (in case (a)) is described.

As an acid, hydrochloric acid, phosphoric acid (including a compound allowing an acidic group to be generated by addition of an alcohol or water, such as diphosphorus pentoxide) and an inorganic acid such as sulfuric acid, an organic acid such as p-toluenesulfonic acid and the like can be employed. The formaldehyde dialkylacetal is employed preferably in the presence of an acid in a solvent or in a solvent-free system. It is further preferred to add a compound allowing any generated alcohol to be removed (for example, diphosphorus pentoxide).

The amount of the formaldehyde dialkylacetal employed per mole of Compound (XXVI) is preferably 0.5 to 50 moles in usual cases, and more preferably 0.8 to 10 moles. The amount of the acid employed per mole of Compound (XXVI) is preferably 0.01 to 10 moles in usual cases, and more preferably 0.05 to 5 moles.

The reaction temperature is preferably 0 degrees C. to 250 degrees C. in usual cases, and more preferably 0 degrees C. to 150 degrees C. The reaction time is preferably 0.1 hour to several days in usual cases, and more preferably 0.5 hour to 2 days.

When the protective group is a t-butyl group (in the case of (b)), it is preferred to conduct a reaction of Compound (XXVI) with isobutene in a solvent in the presence of an inorganic acid such as hydrochloric acid, phosphoric acid, sulfuric acid and the like, or an organic acid such as p-toluenesulfonic acid, trifluoroacetic acid and the like.

The amount of isobutene employed per mole of Compound (XXVI) is preferably 0.5 to 100 moles in usual cases, and more preferably 0.8 to 20 moles. The amount of the acid employed per mole of Compound (XXVI) is preferably 0.01 to 10 moles in usual cases, and more preferably 0.05 to 5 moles.

The reaction temperature is preferably 0 degrees C. to 200 degrees C. in usual cases, and more preferably 0 to 100 degrees C. The reaction time is preferably 0.1 to several days in usual cases, and more preferably 0.5 hour to 2 days.

When the protective group is isopropylidene ketal (in the case of (c)), it is preferred to conduct a reaction of Compound (XXVI) with acetone or acetone dimethyl acetal in a solvent in the presence of an inorganic acid such as hydrochloric acid, phosphoric acid, sulfuric acid and the like, or an organic acid such as p-toluenesulfonic acid, trifluoroacetic acid and the like.

The amount of acetone dimethyl acetal employed per mole of Compound (XXVI) is preferably 0.5 to 100 moles in usual cases, and more preferably 0.8 to 20 moles. The amount of the acid employed per mole of Compound (XXVI) is preferably 0.01 to 10 moles in usual cases, and more preferably 0.05 to 5 moles.

The reaction temperature is preferably 0 degrees C. to 200 degrees C. in usual cases, and more preferably 0 to 100 degrees C. The reaction time is preferably 0.1 hour to several days in usual cases, and more preferably 0.5 hour to 2 days.

(6-3-3) Step 4C3

Next, a reaction for hydrolyzing/decarbonating Compound (XXVII) to obtain Compound (XXII) (Step 4C3) in this Step 4C is described below.

The reaction indicated as Step 4C4 is conducted preferably in the presence of a base in a solvent. The base employed usually includes an alkaline metal base such as sodium hydroxide, potassium hydroxide and the like. The amount of base employed per mole of Compound (XXVII) is preferably 0.1 to 50 moles in usual cases, and more preferably 0.2 to 20 moles.

The solvent may usually be water, as well as water combined with an alcohol and the like, a solvent composition consisting of solvents which do not form a homogenous layer with each other (such as water-toluene). When using a solvent which does not form a homogenous layer, it may sometimes be preferable to use a phase transfer catalyst (for example a customary quaternary ammonium salt) in the reaction system.

The reaction temperature is preferably 0 degrees C. to reflux temperature in usual cases, and more preferably room temperature to reflux temperature. The reaction time is preferably 0.1 hour to several days in usual cases, and more preferably 0.5 hour to 24 hours.

3. Agro-Horticultural Agents and Industrial Material Protecting Agents

The utilities of a 2-(halogenated hydrocarbon-substituted)-5-benzyl-1-azolylmethylcyclopentanol derivatives according to the invention (Compound (I)) as an agro-horticultural agent and an industrial material protecting agent (hereinafter also referred to as “agro-horticultural agent and the like”) are described below.

Since Compound (I) has a 1,2,4-triazolyl group or an imidazolyl group, it forms an acid addition salt of an inorganic acid or an organic acid, as well as a metal complex. Accordingly, Compound (I) can be employed also in the form of such an acid addition salt or the metal complex.

Furthermore, Compound (I) may have at least three asymmetric carbon atoms unless (R^(a))X^(a)n^(a) and (R^(b))X^(b)n^(b) are the same substituents. Thus, depending on the composition, it may be a stereoisomer mixture (enantiomer or diastereomer) or either one of the stereoisomers. Accordingly, at least one of these stereoisomers can be employed also as an active ingredient of an agro-horticultural agent and the like.

(1) Plant Disease Controlling Effects

Compound (I) of the invention exhibits a controlling effect on a broad range of plant diseases. Applicable diseases are exemplified below.

Soybean rust (Phakopsora pachyrhizi, Phakopsora meibomiae), rice blast (Pyricularia grisea), rice brown spot (Cochliobolus miyabeanus), rice leaf blight (Xanthomonas oryzae), rice sheath blight (Rhizoctonia solani), rice stem rot (Helminthosporium sigmoideun), rice bakanae disease (Gibberella fujikuroi), rice bacterial seedling blight (Pythium aphanidermatum), apple powdery mildew (Podosphaera leucotricha), apple scab (Venturia inaequalis), apple blossom blight (Monilinia mali), apple alternaria blotch (Alternaria alternate), apple valsa canker (Valsa mali), pear black spot (Alternaria kikuchiana), pear powdery mildew (Phyllactinia pyri), pear rust (Gymnosporangium asiaticum), pear scab (Venturia nashicola), grape powdery mildew (Uncinula necator), grape downy mildew (Plasmopara viticola), grape ripe rot (Glomerella cingulata), barley powdery mildew (Erysiphe graminis f. sp hordei), barley stem rust (Puccinia graminis), barley stripe rust (Puccinia striiformis), barley stripe (Pyrenophora graminea), barley leaf blotch (Rhynchosporium secalis), wheat powdery mildew (Erysiphe graminis f. sp tritici), wheat leaf rust (Puccinia recondita), wheat stripe rust (Puccinia striiformis), wheat eye spot (Pseudocercosporella herpotrichoides), wheat fusarium blight (Fusarium graminearum, Microdochium nivale), wheat glume blotch (Phaeosphaeria nodorum), wheat leaf blight (Septoria tritici), gourd powdery mildew (Sphaerotheca fuliginea), gourd anthracnose (Colletotrichum lagenarium), cucumber downy mildew (Pseudoperonospora cubensis), cucumber phytophthora rot (Phytophthora capsici), tomato powdery mildew (Erysiphe cichoracearum), tomato early blight (Alternaria solani), eggplant powdery mildew (Erysiphe cichoracearum), strawberry powdery mildew (Sphaerotheca humuli), tobacco powdery mildew (Erysiphe cichoracearum), sugar beet cercpspora leaf spot (Cercospora beticola), maize smut (Ustillaga maydis), plum brown rot (Monilinia fructicola), various plants-affecting gray mold (Botrytis cinerea), sclerotinia rot (Sclerotinia sclerotiorum) and the like may be exemplified. Among these, it exhibits an effect superior to a commercially available metoconazol described in Patent Literature 1 especially against wheat leaf blight (Septoria tritici) which is a critical disease in wheat (see Experimental Example 4 described later in the specification).

Examples of applicable plants may be wild plants, cultivated plant varieties, plants and cultivated plant varieties obtained by conventional biological breeding such as heterologous mating or plasma fusion, and plants and cultivated plant varieties obtained by gene engineering. The gene-engineered plants and the cultivated plant varieties may for example be herbicide-resistant crops, vermin-resistant crops having insecticidal protein-producing genes integrated therein, disease-resistant crops having disease resistance inducer-producing genes integrated therein, palatably improved crops, productively improved crops, preservably improved crops, productively improved crops and the like. The gene-engineered cultivated plant varieties may for example be those involving trade marks such as ROUNDUP READY, LIVERTY LINK, CLEARFIELD, YIELDGARD, HERCULEX, BLLGARD and the like.

(2) Plant Growth Promoting Effect

Furthermore, Compound (I) exhibits yield-increasing effects and quality-improving effects on a broad range of crops and horticultural plants by regulating the growth. Such crops may for example be those listed below.

Wheat, barley, oats, rice, rapeseed, sugarcane, corn, maize, soybean, pea, peanut, sugar beet, cabbage, garlic, radish, carrot, apple, pear, citric fruits such as mandarin, orange, lemon and the like, peach, cherry, avocado, mango, papaya, red pepper, cucumber, melon, strawberry, tobacco, tomato, eggplant, turf, chrysanthemum, azalea, other ornamental plants.

(3) Industrial Material Protecting Effect

Moreover, Compound (I) exhibits an excellent ability of protecting an industrial material from a broad spectrum of hazardous microorganisms which invade such a material. Examples of such microorganisms are listed below.

Paper/pulp deteriorating microorganisms (including slime-forming microorganisms) such as Aspergillus sp., Trichoderma sp., Penicillium sp., Geotrichum sp., Chaetomium sp., Cadophora sp., Ceratostomella sp., Cladosporium sp., Corticium sp., Lentinus sp., Lezites sp., Phoma sp., Polysticus sp., Pullularia sp., Stereum sp., Trichosporium sp., Aerobacter sp., Bacillus sp., Desulfovibrio sp., Pseudomonas sp., Flavobacterium sp. and Micrococcus sp.; fiber-deteriorating microorganisms such as Aspergillus sp., Penicillium sp., Chaetomium sp., Myrothecium sp., Curvularia sp., Gliomastix sp., Memnoniella sp., Sarcopodium sp., Stachybotrys sp., Stemphylium sp., Zygorhynchus sp., Bacillus sp. and Staphylococcus sp.; lumber-deteriorating fungi such as Tyromyces palustris, Coriolus versicolor, Aspergillus sp., Penicillium sp., Rhizopus sp., Aureobasidium sp., Gliocladium sp., Cladosporium sp., Chaetomium sp. and Trichoderma sp.; leather-deteriorating microorganisms such as Aspergillus sp., Penicillium sp., Chaetomium sp., Cladosporium sp., Mucor sp., Paecilomyces sp., Pilobus sp., Pullularia sp., Trichosporon sp. and Tricothecium sp.; rubber/plastic-deteriorating microorganisms such as Aspergillus sp., Penicillium sp., Rhizopus sp., Trichoderma sp., Chaetomium sp., Myrothecium sp., Streptomyces sp., Pseudomonas sp., Bacillus sp., Micrococcus sp., Serratia sp., Margarinomyces sp. and Monascus sp.; paint-deteriorating microorganisms such as Aspergillus sp., Penicillium sp., Cladosporium sp., Aureobasidium sp., Gliocladium sp., Botryodiplodia sp., Macrosporium sp., Monilia sp., Phoma sp., Pullularia sp., Sporotrichum sp., Trichoderma sp., Bacillus sp., Proteus sp., Pseudomonas sp. and Serratia sp.

(4) Formulations

An agro-horticultural formulation containing Compound (I) as an active ingredient may contain various components other than Compound (I). The agro-horticultural formulation containing Compound (I) as an active ingredient can be mixed with a solid carrier, a liquid carrier, a surfactant, and other formulation auxiliary agents. The dosage form of the agro-horticultural formulation containing Compound (I) as an active ingredient may for example be a powder, wettable powder, granule, emulsifiable concentrate and the like.

The agro-horticultural formulation may contain Compound (I) as an active ingredient in an amount of 0.1 to 95% by weight based on the total amount of the agro-horticultural formulation. Compound (I) as an active ingredient is contained preferably in an amount of 0.5 to 90% by weight, and more preferably 2 to 80% by weight.

Carriers, diluents and surfactants employed as formulation auxiliary agents are exemplified below. The solid carriers include talc, kaolin, bentonite, diatomaceous earth, white carbon, clay and the like. The liquid carriers include water, xylene, toluene, chlorobenzene, cyclohexane, cyclohexanone, dimethyl sulfoxide, dimethyl formamide, alcohols and the like. The surfactant may appropriately be selected for an intended effect. The emulsifier may for example be polyoxiethylene alkylaryl ether, polyoxyethylene sorbitan monolaurate and the like, the dispersing agent may for example be lignin sulfonate, dibutylnaphthalene sulfonate and the like, and the wetting agent may for example be an alkyl sulfonate, alkylphenyl sulfonate and the like.

The formulation may be used as it is, or used as being diluted in a diluent such as water to a certain concentration. The concentration of Compound (I) when used as being diluted is preferably 0.001% to 1.0%.

The amount of Compound (I) for 1 ha of the agro-horticultural field such as a farm, paddy field, orchard, greenhouse and the like is 20 to 5000 g, and more preferably 50 to 2000 g. Since these concentration and amount to be used may vary depending on the dosage form, timing of use, method of use, place of use, subject crop and the like, they can be increased or decreased regardless of the ranges mentioned above.

In addition, Compound (I) can be combined with other active ingredients, including bactericides, insecticides, acaricides, herbicides and the like, such as those listed below, thereby enabling the use as an agro-horticultural agent having an enhanced performance.

<Anti-Bacterial Substances>

Acibenzolar-5-methyl, 2-phenylphenol (OPP), azaconazole, azoxystrobin, amisulbrom, bixafen, benalaxyl, benomyl, benthiavalicarb-isopropyl, bicarbonate, biphenyl, bitertanol, blasticidin-S, borax, Bordeaux mixture, boscalid, bromuconazole, bronopol, bupirimate, sec-butylamine, calcium polysulphide, captafol, captan, carbendazim, carboxin, carpropamid, quinomethionate, chloroneb, chloropicrin, chlorothalonil, chlozolinate, cyazofamid, cyflufenamid, cymoxanil, cyproconazole, cyprodinil, dazomet, debacarb, dichlofluanid, diclocymet, diclomezine, dicloran, diethofencarb, difenoconazole, diflumetorim, dimethomorph, dimoxystrobin, diniconazole, dinocap, diphenylamine, dithianon, dodemorph, dodine, edifenphos, epoxiconazole, ethaboxam, ethoxyquin, etridiazole, enestroburin, famoxadone, fenamidone, fenarimol, fenbuconazole, fenfuram, fenhexamid, fenoxanil, fenpiclonil, fenpropidin, fenpropimorph, fentin, ferbam, ferimzone, fluazinam, fludioxonil, flumorph, fluoroimide, fluoxastrobin, fluquinconazole, flusilazole, flusulfamide, flutolanil, flutriafol, folpet, fosetyl-Al, fuberidazole, furalaxyl, furametpyr, fluopicolide, fluopyram, guazatine, hexachlorobenzene, hexaconazole, hymexazol, imazalil, imibenconazole, iminoctadine, ipconazole, iprobenfos, iprodione, iprovalicarb, isoprothiolane, isopyrazam, isotianil, kasugamycin, copper preparations, such as copper hydroxide, copper naphthenate, copper oxychloride, copper sulfate, copper oxide, oxine copper, kresoxim-methyl, mancopper, mancozeb, maneb, mandipropamid, mepanipyrim, mepronil, metalaxyl, metconazole, metiram, metominostrobin, mildiomycin, myclobutanil, nitrothal-isopropyl, nuarimol, ofurace, oxadixyl, oxolinic acid, oxpoconazole, oxycarboxin, oxytetracycline, pefurazoate, orysastrobin, penconazole, pencycuron, penthiopyrad, pyribencarb, fthalide, picoxystrobin, piperalin, polyoxin, probenazole, prochloraz, procymidone, propamocarb, propiconazole, propineb, proquinazid, prothioconazole, pyraclostrobin, pyrazophos, pyrifenox, pyrimethanil, pyroquilon, quinoxyfen, quintozene, silthiopham, simeconazole, spiroxamine, sulfur and sulfur formulations, tebuconazole, tecloftalam, tecnazen, tetraconazole, thiabendazole, thifluzamide, thiophanate-methyl, thiram, thiadinil, tolclofosmethyl, tolylfluanid, triadimefon, triadimenol, triazoxide, tricyclazole, tridemorph, trifloxystrobin, triflumizole, triforine, triticonazole, validamycin, vinclozolin, zineb, ziram, zoxamide, amisulbrom, sedaxane, flutianil, valiphenal, ametoctradin, dimoxystrobin, metrafenone, hydroxyisoxazole, metasulfocarb and the like.

<Insecticides/Acaricides/Nematocides>

Abamectin, acephate, acrinathrin, alanycarb, aldicarb, allethrin, amitraz, avermectin, azadirachtin, azamethiphos, azinphos-ethyl, azinphos-methyl, azocyclotin, Bacillus firmus, Bacillus subtilis, Bacillus thuringiensis, bendiocarb, benfuracarb, bensultap, benzoximate, bifenazate, bifenthrin, bioallethrin, bioresmethrin, bistrifluoron, buprofezin, butocarboxim, butoxycarboxim, cadusafos, carbaryl, carbofuran, carbosulfan, cartap, CGA50439, chlordane, chlorethoxyfos, chlorphenapyr, chlorfenvinphos, chlorfluazuron, chlormephos, chlorpyrifos, chlorpyrifos methyl, chromafenozide, clofentezine, clothianidin, chlorantraniliprole, coumaphos, cryolite, cyanophos, cycloprothrin, cyfluthrin, cyhalothrin, cyhexatin, cypermethrin, cyphenothrin, cyromazine, Cyazapyr, cyenopyrafen, DCIP, DDT, deltamethrin, demeton-5-methyl, diafenthiuron, diazinon, dichlorophen, dichloropropene, dichlorvos, dicofol, dicrotophos, dicyclanil, diflubenzuron, dimethoate, dimethylvinphos, dinobuton, dinotefuran, emamectin, endosulfan, EPN, esfenvalerate, ethiofencarb, ethion, ethiprole, ethofenprox, ethoprophos, etoxazole, famphur, fenamiphos, fenazaquin, fenbutatin oxide, fenitrothion, fenobucarb, fenothiocarb, fenoxycarb, fenpropathrin, fenpyroximate, fenthion, fenvalerate, fipronil, flonicamid, fluacrypyrim, flucycloxuron, flucythrinate, flufenoxuron, flumethrin, fluvalinate, flubendiamide, formetanate, fosthiazate, halfenprox, furathiocarb, halofenozide, gamma-HCH, heptenophos, hexaflumuron, hexythiazox, hydramethylnon, imidacloprid, imiprothrin, indoxacarb, isoprocarb, isoxathion, lufenuron, malathion, mecarbam, metam, methamidophos, methidathion, methiocarb, methomyl, methoprene, methothrin, methoxyfenozide, metolcarb, milbemectin, monocrotophos, naled, nicotine, nitenpyram, novaluron, noviflumuron, omethoate, oxamyl, oxydemethon methyl, parathion, permethrin, phenthoate, phorate, phosalone, phosmet, phosphamidon, phoxim, pirimicarb, pirimiphos-methyl, profenofos, propoxur, prothiophos, pymetrozin, pyrachlophos, pyrethrin, pyridaben, pyridalyl, pyrimidifen, pyriproxifen, pyrifluquinazon, pyriprole, quinalphos, silafluofen, spinosad, spirodiclofen, spiromesifen, spirotetramat, sulfluramid, sulphotep, SZI-121, tebufenozid, tebufenpyrad, tebupirimphos, teflubenzuron, tefluthrin, temephos, terbufos, tetrachlorvinphos, thiacloprid, thiamethoxam, thiodicarb, thiofanox, thiometon, tolfenpyrad, tralomethrin, tralopyril, triazamate, triazophos, trichlorfon, triflumuron, vamidothion, valifenal, XMC, xylylcarb, imicyafos, lepimectin and the like.

<Plant Growth Regulators>

Ancymidol, 6-benzylaminopurine, paclobutrazol, diclobutrazole, uniconazole, methylcyclopropene, mepiquat chloride, ethefon, chlormequat chloride, inabenfide, prohexadione and its salts, trinexapac-ethyl and the like. As plant hormones, jasmonic acid, brassinosteoid, gibberellin and the like.

An industrial material protecting agents containing Compound (I) as an active ingredient may contain various components other than Compound (I). The industrial material protecting agents containing Compound (I) as an active ingredient can be used as being dissolved or dispersed in a suitable liquid carrier or as being mixed with a solid carrier. The industrial material protecting agents containing Compound (I) as an active ingredient may further contain an emulsifier, dispersing agent, spreading agent, penetrating agent, wetting agent, stabilizer and the like. The dosage form of the industrial material protecting agents containing Compound (I) as an active ingredient may for example be a wettable powder, powder, granule, tablet, paste, suspension, spray and the like. The industrial material protecting agents containing Compound (I) as an active ingredient may contain other biocides, insecticides, deterioration-preventing agent and the like.

The liquid carrier may be any liquid as long as it does not react with an active ingredient. The liquid carrier may for example be water, alcohols (for example, methyl alcohol, ethyl alcohol, ethylene glycol, cellosolve and the like), ketones (for example, acetone, methylethylketone and the like), ethers (for example, dimethyl ether, diethyl ether, dioxane, tetrahydrofuran and the like), aromatic hydrocarbons (for example, benzene, toluene, xylene, methylnaphthalene and the like), aliphatic hydrocarbons (for example, gasoline, kerosene, paraffin oil, machine oil, fuel oil and the like), acid amides (for example, dimethyl formamide, N-methylpyrrolidone and the like), halogenated hydrocarbons (for example, chloroform, carbon tetrachloride and the like), esters (for example, acetic acid ethyl ester, fatty acid glycerin ester and the like), nitriles (for example, acetonitrile and the like), and dimethyl sulfoxide and the like.

The solid carrier may for example be a microparticle or a granule of kaolin clay, bentonite, acid clay, pyrophylite, talc, diatomaceous earth, calcite, urea, ammonium sulfate and the like.

The emulsifiers and the dispersing agents may for example be soaps, alkyl sulfonates, alkylaryl sulfonates, dialkyl sulfosuccinates, quaternary ammonium salts, oxyalkylamines, fatty acid esters, polyalkylene oxide-based, anhydrosorbitol-based surfactants.

When Compound (I) is contained as an active ingredient in a formulation, it is added in such an amount that the concentration becomes 0.1 to 99.9% by weight based on the entire amount of the formulation, although the content may vary depending on the dosage form and the purpose of use. Upon being used practically, it is combined appropriately with a solvent, diluent, extender and the like so that the treatment concentration is usually 0.005 to 5% by weight, and preferably 0.01 to 1% by weight.

As described above, an azole derivative represented by Compound (I) exhibits an excellent biocidal effect on a large number of microorganisms which induce diseases in plants. Thus, an agro-horticultural disease controlling agent containing Compound (1) as an active ingredient has a low toxicity to humans and animals, are capable of being handled safely, and exhibits a high controlling effect on a wide range of plant diseases.

(Remarks)

The invention is not limited to the embodiments described above, and it may be varied in various ways within the scope of the appended Claims. Thus, an embodiment achieved by combining technical means varied appropriately within the scope of the appended Claims will be included by the technical scope of the invention.

EXAMPLES

The invention is embodied below with referring to Production Examples, Formulation Examples, and Experimental Examples. The invention is not restricted to the following Production Examples, Formulation Examples, and Experimental Examples unless departing from its scope.

Production Example 1 Synthesis of (1RS,2SR,5SR)-5-(4-chlorobenzyl)-2-chloromethyl-2-methyl-1-(1H-1,2,4-triazol-1-yl methyl)cyclopentanol (Compound No. I-1 (Compound (I), (R^(a))X^(a)n^(a)=CH₃, (R^(b))X^(b)n^(b)=CH₂Cl, Ym=4-Cl, A=N, isomer type: C)) (Production by Step 1A in First Production Method)

Under argon atmosphere, (1RS,2RS,3SR)-p-toluenesulfonic acid

3-(4-chlorobenzyl)-2-hydroxy-1-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)cyclopentyl) methyl ester (Compound No. II-1 (Compound (II), (R^(a1))X^(a1)n^(a1) (L^(a))p^(a)=CH₃, (R^(b1))X^(b1)n^(b1) (L^(b))p^(b)=CH₂OTos, Ym=4-Cl, A=N, isomer type: C)) (12.0 mg, 0.0245 mmol) was dissolved in dehydrated DMF (0.24 ml). Lithium chloride (10.4 mg, 0.245 mmol) was added, and stirring was conducted for 1.5 hours at 100 degrees C. To the reaction solution, ethyl acetate (2 ml) was added, washed with saturated brine (0.5 ml×5). The organic layer was dried over anhydrous sodium sulfate, and then concentrated. Silica gel column chromatography (eluent; hexane:ethyl acetate=1:2) was employed for purification to obtain an intended substance.

Product: 5.0 mg

Yield: 58%

Description: White solid, Melting point (m.p.) 139-140 degrees C.

¹H-(400 MHz, CDCl₁) delta:

1.18 (3H, s), 1.46 (2H, m), 1.70 (1H, m), 1.92 (2H, m),2.35 (2H, m). 3.26 (1H, d, J=10.8 Hz), 3.57 (1H, d, J=10.8 Hz), 4.06 (1H, s), 4.25 (1H, d, J=14.2 Hz), 4.54 (1H, d, J=14.2 Hz), 6.98 (2H, d, J=8.4 Hz), 7.21 (2H, d, J=8.4 Hz), 8.02 (1H, s), 8.19 (1H, s).

Compound (I) can also be produced from Intermediate (XVI) as shown below in accordance with the third production method described above. As an example, the production of I-1 is shown below.

Synthesis of (1RS,2SR,5SR)-5-(4-chlorobenzyl)-2-chloromethyl-2-methyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol (Compound No. I-1 (Compound (I), (R^(a))X^(a)n^(a)=CH₃, (R^(b))X^(b)n^(b)=CH₂Cl, Ym=4-Cl, A=N, isomer type: C)) (Production by Step 3A in Third Production Method)

(1RS,4SR,5RS)-4-(4-Chlorobenzyl)-1-methyl-5-(1H-1,2,4-triazol-1-ylmethyl)-6-oxa bicyclo[3,2,0]heptane Compound No. XVI-1 (Compound (XVI), [(R^(a2))X^(a2)n^(a2) (OR³)p^(a1)]=CH₃, Ym=4-Cl, A=N, isomer type: C) (20.79 g, 62.3 mmol) was dissolved in DMF (200 ml), and heated to 80 degrees C. To this, lithium chloride (39.59 g, 934 mmol) and p-toluenesulfonic acid monohydrate (14.20 g, 74.8 mmol) were added, and stirring was conducted for 1.5 hours. After completion of the reaction, DMF was distilled away under reduced pressure, the residue was combined with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled away, and the residue was recrystallized from ethyl acetate/hexane to obtain the desired substance.

Product: 22.24 g

Yield: 95.9%

The melting point and the NMR spectrum of Compound I-1 produced in this method were in complete agreement with that synthesized by the method described above.

Production Example 2 Synthesis of (1RS,2RS,5SR)-5-(4-chlorobenzyl)-2-chloromethyl-2-methyl-1-(1H-1,2,4-triazol-1-yl methylcyclopentanol (Compound No. I-101 (Compound (I), (R^(a))X^(a)n^(a)=CH₂Cl, (R^(b))X^(b)n^(b)=CH₃, Ym=4-Cl, A=N, isomer type: C))

Under argon atmosphere, (1RS,2SR,3RS)-p-toluenesulfonic acid 3-(4-chlorobenzyl)-2-hydroxy-1-methyl-2-(1H-1,2,4-triazol-lylmethyecyclopentyl methyl ester (Compound No. II-2 (Compound (II), (R^(a1))X^(a1)n^(a1) (L^(a))p^(a)=CH₂OTos, (R^(b1))X^(b1)n^(b1) (L^(b))p^(b)=CH₃, Ym=4-Cl, A=N, isomer type: C)) (10.6 mg, 0.216 mmol) was dissolved in dehydrated DMF (0.21 ml). Lithium chloride (9.2 mg, 0.216 mmol) was added, and stirring was conducted for 3 hours at 100 degrees C. To the reaction solution, ethyl acetate (2 ml) was added, and washing with saturated brine (0.5 ml×5) was conducted. The organic layer was dried over anhydrous sodium sulfate, and then concentrated. Silica gel column chromatography (eluent; hexane:ethyl acetate=1:1) was employed for purification to obtain an intended substance.

Product: 4.6 mg

Yield: 60%

Description: White solid, Melting point (m.p.) 124 degrees C.

¹H-NMR (400 MHz, CDCl₃) delta:

0.81 (3H, s), 1.41-1.77 (4H, m), 2.30 (1H. m), 2.42 (1H, dd, J=13.6, 4.7 Hz), 2.51 (1H, dd, J=13.6, 10.1 Hz), 3.52 (1H, d, J=11.1 Hz), 3.61 (1H, d, J=11.1 Hz), 3.98 (1H, s), 4.24 (1H, d, J=14.2 Hz), 4.38 (1H, d, J=14.2 Hz). 7.03 (2H, d, J=8.4 Hz), 7.22 (2H, d, J=8.4 Hz), 7.99 (1H, s), 8.20 (1H, s).

Production Example 3 Synthesis of (1RS,2SR,5SR)-2-bromomethyl-5-(4-chlorobenzyl)-2-methyl-1-(1H-1,2,4-triazol-1-yl methyl)cyclopentanol (Compound No. I-25 (Compound (I), (R^(a))X^(a)n^(a)=CH₃. (R^(b))X^(b)n^(b)=CH₂Br, Ym=4-Cl, A=N, isomer type: C))

(1RS,2RS,3SR)-p-Toluenesulfonic acid 3-(4-chlorobenzyl)-2-hydroxy-1-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)cyclopentylmethyl ester (Compound No. II-1 (Compound (II), (R^(a1))X^(a1)n^(a1) (L^(a))p^(a)=CH₃, (R^(b1))X^(b1)n^(b1) (L^(b))p^(b)=CH₂OTos, Ym=4-Cl, A=N, isomer type: C)) (400 mg, 0.8163 mmol) was dissolved in dehydrated DMF (8 ml) under argon atmosphere. Lithium bromide (756 mg, 8.706 mmol) was added, and stirring was conducted for 8 hours at 60 degrees C. The reaction solution was cooled, ethyl acetate (66 ml) was added, and washing with saturated brine (20 ml×3) was conducted. The organic layer was dried over anhydrous sodium sulfate, and then concentrated. Silica gel chromatography (eluent; hexane:ethyl acetate=1:2) was employed for purification to obtain an intended substance.

Product: 56 mg

Yield: 17%

Description: Solid, m.p. 235-236 degrees C.

¹H-NMR (400 MHz, CDCl₃) delta:

1.19 (3H, s), 1.41-1.53 (2H, m), 1.65-1.75 (1H, m), 1.91-2.04 (2H, m), 2.32-2.41 (2H, m), 2.96 (1H, d, J=9.9 Hz), 3.54 (1H, d, J=9.9 Hz), 4.09 (1H, s), 4.23 (1H, d, J=14.2 Hz), 4.50 (1H, d, J=14.2 Hz), 6.99 (2H, d, J=8.4 Hz), 7.21 (2H, d, J=8.4 Hz), 8.01 (1H, s), 8.18 (1H, s).

Production Example 4 Synthesis of (1RS,2SR,5SR)-5-(4-chlorobenzyl)-2-(2-chloroethyl)-2-methyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol (Compound No. I-104 (Compound (I), (R^(a))X^(a)n^(a)=CH₂CH₂Cl, (R^(b)) X^(b)n^(b)=CH₃, Ym=4-Cl, A=N, isomer type: C)) p-Toluenesulfonic acid

2-[(1RS,2SR,3RS)-3-(4-chlorobenzyl)-2-hydroxy-1-methyl-2-(1H-1,2,4-triazol-lylmethyl)cyclopentyl]ethyl ester (Compound No. II-3 (Compound (II), (R^(a1))X^(a1)n^(a1) (L^(a))p^(a)=CH₃, (R^(b1))X^(b1)n^(b1) (L^(b))p^(b)=CH₂CH₂OTos, Ym=4-Cl, A=N, isomer type: C)) (42 mg, 0.084 mmol) was dissolved in DMF (1 ml). Lithium chloride (33 mg, 0.77 mmol) was added, and stirring was conducted for 4 hours at 80 degrees C. The solvent was distilled away, and ethyl acetate was added. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated. Silica gel column chromatography (eluent; chloroform:ethyl acetate=1:2) was employed for purification to obtain an intended substance.

Product: 22 mg

Yield: 71%

Description: Colorless liquid

¹H-NMR (400 MHz, CDCl₃) delta:

0.66 (3H, s), 1.43-1.53 (2H, m), 1.61-1.74 (2H, m). 1.83-1.89 (2H, m), 2.18-2.26 (1H, m), 2.40 (1H, dd, J=13.6, 4.9 Hz), 2.48 (1H, dd, J=13.6, 10.0 Hz), 3.46-3.57 (2H, m), 4.01 (1H, s), 4.16 (1H, d, J=14.1 Hz), 4.18 (1H, d, J=14.1 Hz), 7.01 (2H, d, J=8.4 Hz), 7.21 (2H, d, J=8.4 Hz), 7.99 (1H, s), 8.16 (1H, s).

Production Example 5 Synthesis of (1RS,2SR,5SR)-5-(4-chlorobenzyl)-2-trifluoromethyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol (Compound No. I-65 (Compound (I), (R^(a))X^(a)n^(a)=H, (R^(b))X^(b)n^(b)=CF₃, Ym=4-Cl, A=N, isomer type: C)) and

(1RS,2SR,5RS)-5-(4-chlorobenzyl)-2-trifluoromethyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol (Compound No. I-365 (Compound (I), (R^(a))X^(a)n^(a)=H, (R^(b))X^(b)n^(b)=CF₃, Ym=4-Cl, A=N, isomer type: T))

(1) Synthesis of Intermediate 7-(4-chlorobenzyl)-4-trifluoromethyl-1-oxaspiro[2.4]heptane (Compound (III), (R^(a))X^(a)n^(a)=H, (R^(b))X^(b)n^(b)=CF₃, Ym=4-Cl)

Under nitrogen flow, anhydrous THF (1 ml) was combined with Sm (705 mg, 4.7 mmol), and a solution of 1,2-diiodoethane (662 mg, 2.3 mmol) dissolved in anhydrous THF (2 ml) was added dropwise with stirring. The reaction solution was stirred for 30 minutes at room temperature. Thereafter, while cooling with ice, a solution of diiodomethane (723 mg, 2.7 mmol) and 5-(4-chlorobenzyl)-2-trifluoromethylcyclopentanone (Compound (V), (R^(a))X^(a)n^(a)=H, (R^(b)) X^(b)n^(b)=CF₃, Ym=4-Cl) (432 mg, 1.6 mmol) dissolved in anhydrous THF (2 ml) was added dropwise, and stirring was continued for 2 hours at room temperature. The reaction solution was poured into a solution mixture of an aqueous solution of NaOH (NaOH (1.1 g) dissolved in 10 ml of water) and THF (10 ml), and stirring was continued for 30 minutes at room temperature. This reaction solution was combined with ice, neutralized with a 1N aqueous solution of hydrochloric acid, and then extracted with hexane. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure. Silica gel chromatography (eluent; hexane:ethyl acetate=70:1) was conducted for purification to obtain the desired substance.

Product: 111 mg

Yield: 24%

Description: Yellow oil

¹H-NMR (400 MHz, CDCl₃) delta:

1.46-2.07 (m, 4H), 2.35-2.45 (m, 2H), 2.57-2.90 (m, 2H), 2.72 (d, J=4.8 Hz), 2.90 (d, J=4.8 Hz), 7.09 (m, 2H), 7.24 (d, 2H, J=8.4 Hz).

(2) Synthesis of Compound No. I-65 and Compound No. I-365

60% Sodium hydride 24 mg (0.60 mmol) washed with hexane was suspended in anhydrous DMF (0.4 ml), and 39 mg (0.56 mmol) of 1H-1,2,4-triazole was added while cooling with ice. After stirring for 20 minutes at room temperature, a solution of Compound (III) (111 mg, 0.38 mmol) synthesized above in anhydrous DMF (0.6 ml) was added, and stirring was conducted with heating at 95 degrees C. for 3 hours. The reaction solution was poured into ice/water and extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and saturated brine, and then dried over anhydrous sodium sulfate. Under reduced pressure, the solvent was distilled away, and the crude product was purified by silica gel chromatography (eluent; hexane:ethyl acetate=2:3 to 1:7) to obtain the desired substance.

<Compound No. I-65>

Product: 43 mg

Yield: 31%

Description: Yellowish orange oil

¹H-NMR (400 MHz, CDCl₃) delta:

1.63 (2H, m), 1.84 (1H, m), 2.00 (2H, m), 2.44 (1H, dd-like, J=13.4, 10.4 Hz), 2.57 (1H, dd-like, J=13.4, 4.4 Hz), 2.64 (1H, m), 2.81 (1H, bs), 4.37 (1H, d, J=14.2 Hz), 4.42 (1H, d, J=14.2 Hz), 7.08 (2H, d, J=8.2 Hz), 7.24 (d, 2H, J=8.2 Hz), 8.01 (s, 1H), 8.10 (s, 1H).

<Compound No. I-365>

Product: 10 mg

Yield: 7%

Description: Yellowish orange oil

¹H-NMR (400 MHz, CDCl₃) delta:

1.35 (2H, m), 1.91 (2H, m), 2.28 (2H. m), 2.51 (1H, m), 3.14 (1H, d-like, J=10.0 Hz), 3.89 (1H, bs), 4.28 (1H, d J=14.0 Hz), 4.39 (1H, d, J=14.0 Hz), 7.07 (2H, d, J=8.2 Hz), 7.26 (d, 2H, J=8.2 Hz), 8.02 (s, 1H), 8.22 (s, 1H).

Production Example 6 Synthesis of (1RS,2RS,5SR)-5-(4-chlorobenzyl)-2-(2-chloropropenyl)-2-methyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol (Compound No. I-15 (Compound (I), (R^(a))X^(a)n^(a)=CH₃, (R^(b))X^(b)n^(b)=CH₂CCl═CH₂, Ym=4-Cl, A=N, isomer type: C)) and (1RS,2SR,5SR)-5-(4-chlorobenzyl)-2-(2-chloropropenyl)-2-methyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol (Compound No. I-115 (Compound (I), (R^(a))X^(a)n^(a)=CH₂CCl═CH₂, (R^(b))X^(b)n^(b)=CH₃, Ym=4-Cl, A=N, isomer type: C)) (1) Synthesis of intermediate 7-(4-chlorobenzyl)-4-(2-chloropropenyl)-4-methyl-1-oxaspiro[2.4]heptane (Compound (R^(a))X^(a)n^(a)=CH₃, (R^(b))X^(b)n^(b)=CH₂CCl═CH₂, Ym=4-Cl)

Under argon atmosphere, anhydrous THF (9 ml) was combined with Sm (1.01 g, 6.71 mmol), and then, at room temperature, 1,2-diiodoethane (1.05 g, 3.73 mmol) was added. The reaction solution was stirred for 1 hour at room temperature, and then cooled to −7 degrees C. to −2 degrees C., and 2-(2-chloro-2-propenyl)-5-(4-chlorobenzyl)-2-methylcyclopentanone (Compound (V), (R^(a))X^(a)n^(a)=CH₃, (R^(b))X^(b)n^(b)=CH₂CCl═CH₂, Ym=4-Cl) dissolved in diiodomethane (0.90 g, 0.00168×2.0 mol) and THF (5 ml) was added, and stirred for 1.5 hours at the same temperature. To this, a 2N aqueous solution of NaOH (8 ml) was added, and stirring was conducted for 1 hour while cooling with ice. A 2N aqueous solution of hydrochloric acid (8 ml) was added, and then extraction with hexane (100 ml×2) was conducted. The organic layer was washed with water (50 ml) and saturated brine (30 ml), and then dried over anhydrous sodium sulfate and concentrated to obtain a crude intended substance (0.44 g), which was used in the next reaction as it was.

(2) Synthesis of Compound No. 1-15 and Compound No. I-115

A crude compound (III) (0.24 g, 0.77 mmol) synthesized above was dissolved in DMF (1.5 ml), and potassium carbonate (0.108 g, 0.781 mmol) and 1H-1,2,4-triazole (0.053 g, 0.77 mmol) was added, and stirring was conducted at about 80 degrees C. for 2 hours and at about 90 degrees C. for 2 hours. To the reaction solution, ethyl acetate (50 ml) and water (30 ml) was added, and then partitioned. The aqueous layer was extracted with ethyl acetate (50 ml), and then the organic layer was washed with saturated brine (50 ml), and then dried over anhydrous sodium sulfate, and concentrated. A silica gel column (eluent; hexane:ethyl acetate=2:1 to 1:2) was employed for purification to obtain an intended substance.

<Compound No. I-15>

Product: 15 mg

Yield: 4%

Description: Yellow oil

¹H-NMR (400 MHz, CDCl₃) delta:

1.11 (3H, s), 1.40-2.50 (8H, m), 2.59 (1H, d, J=14.0 Hz), 3.82 (1H. s), 4.23 (1H, d, J=14.2 Hz), 4.33 (1H, d, J=14.2 Hz), 5.02 (1H, s), 5.20 (1H, s), 6.99-7.07 (2H, m), 7.18-7.25 (2H, m), 8.01 (1H, s), 8.19 (1H, s).

<Compound No. I-115>

Product: 60 mg

Yield: 16%

Description: Yellow oil

¹H-NMR (400 MHz, CDCl₃) delta:

0.75 (3H, s), 1.40-1.58 (1H, m), 1.62-1.83 (3H, m), 2.15-2.53 (5H, m), 3.72 (1H, s), 4.14 (1H, d, J=14.1 Hz), 4.25 (1H, d, J=14.1 Hz), 5.12 (1H, d, J=1.1 Hz), 5.32 (1H, d, J=1.1 Hz), 6.99-7.06 (2H, m), 7.18-7.26 (2H, m), 7.99 (1H, s), 8.16 (1H, s).

While these isomers may exist in 4 types with regard to the relative steric configuration, 2 types was produced, and the hydroxyl group and the benzyl group in 5-position was considered to be in a cis configuration based on the reactivity with samarium iodide, and accordingly, the isomer type was assumed to be and assigned to C, although there is a possibility of isomer type T (Compound No. I-315 and I-415).

Production Example 7 Synthesis of (1RS,2SR,5SR)-5-(4-chlorobenzyl)-2-chloromethyl-2-ethyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol (Compound No. I-36 (Compound (I), (R^(a))X^(a)n^(a)=CH₂CH₃, (R^(b))X^(b)n^(b)=CH₂Cl, Ym=4-Cl, A=N, isomer type: C))

(1RS,2RS,3SR)-p-Toluenesulfonic acid 3-(4-chlorobenzyl)-1-ethyl-2-hydroxy-2-(1H-1,2,4-triazol-1-yl)methylcyclopentylmethyl ester (Compound No. II-4 (Compound (II), (R^(a1))X^(a1)n^(a1) (L^(a))p^(a)=CH₂CH₃, (R^(b1))X^(b1)n^(b1) (L^(b))p^(b)=CH₂OTos, Ym=4-Cl, A=N, isomer type: C)) (56.1 mg, 0.111 mmol) was dissolved in DMF (1.1 ml), and lithium chloride (47.2 mg, 1.11 mmol) was added, and stirring was conducted for 30 minutes at 80 degrees C. After completion of the reaction, water was added, and extraction with ethyl acetate was conducted. The organic layer was washed with saturated brine, and then washed with anhydrous sodium sulfate. The solvent was distilled away, and the residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=1:3) for purification to obtain the desired substance.

Product: 3.0 mg

Yield: 7%

Description: White solid, Melting point (m.p.) 113.0 degrees C.

¹H-NMR (400 MHz, CDCl₃) delta:

0.94 (3 Ht, J=7.3 Hz), 1.31-1.46 (2H, m), 1.49 (1H, dd, J=13.0, 3.2 Hz), 1.50-1.63 (3H, m), 1.79-1.80 (1H, m), 2.13 (1H, dd, J=13.0, 11.5 Hz), 2.23-2.31 (1H, m), 3.50 (1H, d, J=11.4 Hz), 4.03 (1H, s), 4.09 (1H, d. J=11.4 Hz). 4.34 (1H, d, J=14.2 Hz), 4.79 (1H, d, J=14.2 Hz), 6.88 (2H, d, J=8.4 Hz), 7.17 (2H, d, J=8.4 Hz), 8.01 (1H, s), 8.21 (1H, s).

Production Example 8 Synthesis of cis-5-(4-chlorobenzyl)-2,2-bis(chloromethyl)-1-(1H-1,2,4-triazol-1-yl)methylcyclopentanol (Compound No. I-203 (Compound (I), (R^(a))X^(a)n^(a)=CH₂Cl, (R^(b))X^(b)n^(b)=CH₂Cl, Ym=4-Cl, A=N, isomer type: C))

cis-5-(4-Chlorobenzyl)-2,2-bis(methanesulfonyloxymethyl)-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol (Compound No. II-5 (Compound (II), (R^(a1))X^(a1)n^(a1) (L^(a))p^(a)=CH₂OMs, (R^(b1))X^(b1)n^(b1) (L^(b))p^(b)=CH₂OMs, Ym=4-Cl, A=N, isomer type: C)) (73.9 mg, 0.136 mmol) was dissolved in DMF (1.5 ml) and lithium chloride (57.8 mg, 1.42 mmol) was added, and then stirring was conducted for 7 hours at 80 degrees C. To this, p-toluenesulfonic acid monohydrate (12.9 mg, 0.68 mmol) was added, and then stirring was conducted further for 4 hours. After completion of the reaction, water was added, and extraction with ethyl acetate was conducted. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled away, and the residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=1:1) for purification to obtain the desired substance.

Product: 9.7 mg

Yield: 18%

Description: Colorless viscous liquid

¹H-NMR (400 MHz, CDCl₃) delta:

1.45-1.55 (1H, m), 1.61-1.75 (2H, m), 1.86-1.95 (1H, m), 2.26-2.37 (2H, m), 3.72 (1H, d, J=11.7 Hz), 3.73 (1H, d, J=11.3 Hz), 3.80 (1H, d, J=11.3 Hz), 3.82 (1H, d, J=11.7 Hz), 4.30 (1H, d, J=14.1 Hz), 4.54 (1H, s), 4.78 (1H, d, J=14.1 Hz), 6.93 (2H, d, J=8.4 Hz), 7.19 (2H, d, J=8.4 Hz), 8.02 (1H, s), 8.22 (1H, s).

Production Example 9 Synthesis of (1RS,2SR,5RS)-5-(4-chlorobenzyl)-2-chloromethyl-2-methyl-1-[1,2,4]triazol-1-ylmethylcyclopentanol (Compound No. I-301 (Compound (I), (R^(a))X^(a)n^(a)=CH₃, (R^(b))X^(b)n^(b)=CH₂Cl, Ym=4-Cl, A=N, isomer type: T))

(1RS,4RS,5RS)-4-(4-Chlorobenzyl)-1-methyl-5-(1H-1,2,4-triazol-1-ylmethyl)-6-oxa bicyclo[3,2,0]heptane (Compound No. (XVI)-2, (Compound (XVI), (R^(a))X^(a)n^(a)=CH₃, Ym=4-Cl, A=N, isomer type: T)) (150.1 mg, 0.472 mmol) was dissolved in DMF (3 ml), and lithium chloride (300.3 mg, 7.08 mmol) and p-toluenesulfonic acid monohydrate (107.7 mg, 0.566 mmol) were added, and stirring was conducted for 1.5 hours at 80 degrees C. After completion of the reaction. DMF was distilled away under reduced pressure, the residue was combined with aqueous saturated sodium hydrogen carbonate and water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, the solvent was distilled away, and the residue was recrystallized from ethyl acetate/hexane to obtain the desired substance.

Product: 130.1 mg

Description: Colorless crystal, Melting point (m.p.) 133.8 degrees C.

Yield: 77.8%

¹H-NMR (400 MHz, CDCl₃) delta:

1.23 (3H, s), 1.34-1.43 (1H, m), 1.61-1.69 (1H, m), 1.74-1.83 (1H, m), 1.86-1.94 (1H, m), 2.20-2.29 (1H, m), 2.33 (1H, t, J=12.1 Hz), 2.93 (1H, dd, J=12.1, 2.8 Hz), 3.56 (1H, d, J=10.9 Hz), 3.63 (1H, d, J=10.9 Hz), 4.19 (1H, s). 4.47 (1H, d, J=14.2 Hz), 4.52 (1H, d, J=14.2 Hz), 6.95 (2H, d, J=8.3 Hz), 7.21 (2H, d, J=8.3 Hz), 8.03 (1H, s), 8.21 (1H, s).

Production Example 10 Synthesis of (1RS,2RS,5RS)-5-(4-chlorobenzyl)-2-chloromethyl-2-methyl-1-[1,2,4]triazol-1-ylmethylcyclopentanol (Compound No. I-401 (Compound (I), (R^(a))X^(a)n^(a)=CH₂Cl, (R^(b))X^(b)n^(b)=CH₃, Ym=4-Cl, A=N, isomer type: T))

(1RS,2SR,5RS)-5-(4-Chlorobenzyl)-2-(p-toluenesulfonyl)oxymethyl-2-methyl-1-[1,2,4]triazol-1-ylmethylcyclopentanol (Compound No. II-6 (Compound (II), (R^(a1))X^(a1)n^(a1) (L^(a))p^(a)=CH₂OTos, (R^(b1))X^(b1)n^(b1) (L^(b))p^(b)R^(b1)═CH₃, Ym=4-Cl, A=N, isomer type: T)) (215.7 mg, 0.440 mmol) was dissolved in DMF (4 ml), and lithium chloride (280 mg, 6.60 mmol) was added, and stirring was conducted for 3.5 hours at 80 degrees C. After completion of the reaction, the solvent was distilled away, water was added and extraction with ethyl acetate was conducted. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled away, and the residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=1:2) for purification to obtain the desired substance.

Product: 34.4 mg

Yield: 22.2%

Description: Colorless viscous liquid

¹H-NMR (400 MHz, CDCl₃) delta:

1.08 (3H, s), 1.29-1.39 (1H, m), 1.63-1.70 (1H, m), 1.71-1.82 (2H. m), 2.16 (1H, t, J=12.8 Hz), 2.39-2.46 (1H, m), 2.80 (1H, dd, J=12.8, 3.3 Hz), 3.47 (1H, d, J=11.1 Hz), 3.62 (1H, d, J=11.1 Hz), 3.80 (1H, s), 4.46 (2H, s), 7.03 (2H, d, J=8.4 Hz), 7.22 (2H, d, J=8.4 Hz), 7.99 (1H, s), 8.30 (1H, s).

Production Example 11 Synthesis of (1RS,2SR,5SR)-5-(3-chlorobenzyl)-2-chloromethyl-2-methyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol (Compound No. I-74 (Compound (I), (R^(a))X^(a)n^(a)=CH₃. (R^(b))X^(b)n^(b)=CH₂Cl, Ym=3-Cl, A=N, isomer type: C))

(1RS,4SR,5RS)-4-(3-Chlorobenzyl)-1-methyl-5-(1H-1,2,4-triazol-1-ylmethyl)-6-oxa bicyclo[3,2,0]heptane (Compound No. (XVI)-3, (Compound (XVI), (R^(a))X^(a)n^(a)=CH₃, Ym=3-Cl, A=N, isomer type: C)) (370 mg, 1.16 mmol) was dissolved in DMF (7 ml) and heated to 80 degrees C. To this, lithium chloride (589 mg, 13.9 mmol) and p-toluenesulfonic acid monohydrate (264 mg. 1.39 mmol) were added, and stifling was conducted for 135 minutes. After completion of the reaction, the residue was combined with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, the solvent was distilled away, and the residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=1:1) for purification to obtain the desired substance.

Product: 309 mg

Yield: 75.2%

Description: Colorless viscous liquid

¹H-NMR (CDCl₃) delta:

1.19 (3H, s), 1.41-1.53 (2H, m), 1.66-1.75 (2H, m). 1.90-1.99 (2H, m), 2.32-2.41 (2H, m), 3.24 (1H, d, J=10.8 Hz), 3.57 (1H, d, J=10.8 Hz), 4.10 (1H, s), 4.26 (1H, d, J=14.2 Hz), 4.54 (1H, d, J=14.2 Hz), 6.93 (1H, d, J=6.6 Hz), 7.05 (1H, s), 7.13-7.19 (2H, m), 8.02 (1H, s), 8.20 (1H, s).

Production Example 12 Synthesis of (1RS,2SR,5SR)-2-chloromethyl-5-(4-fluorobenzyl)-2-methyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol (Compound No. I-77 (Compound (I), (R^(a))X^(a)n^(a)=CH₃, (R^(b))X^(b)n^(b)=CH₂Cl, Ym=4-F, A=N, isomer type: C))

(1RS,4SR,5RS)-4-(4-Fluorobenzyl)-1-methyl-5-(1H-1,2,4-triazol-1-ylmethyl)-6-oxa bicyclo[3,2,0]heptane (Compound No. (XVI)-4, (Compound (XVI), (R^(a))X^(a)n^(a)=CH₃, Ym=4-F, A=N, isomer type: C)) (201.1 mg, 0.667 mmol) was dissolved in DMF (2 ml), and heated to 80 degrees C. To this, lithium chloride (339.3 mg, 8.00 mmol) and p-toluenesulfonic acid monohydrate (152.3 mg, 0.800 mmol) were added, and stirring was conducted for 1 hour. After completion of the reaction, the residue was combined with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, the solvent was distilled away, and the residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=1:3) for purification to obtain the desired substance.

Product: 224.3 mg

Yield: 99.6%

Description: White solid, Melting point (m.p.) 126.5 degrees C.

¹H-NMR (CDCl₃) delta:

1.18 (3H, s), 1.41-1.53 (2H, m), 1.65-1.76 (1H, m),1.89-1.98 (2H, m), 2.28-2.38 (2H, m), 3.26 (1H, d, J=10.8 Hz), 3.57 (1H, d, J=10.8 Hz), 4.05 (1H, s), 4.25 (1H, d, J=14.2 Hz), 4.54 (1H, d, J=14.2 Hz), 6.92 (2H, t, J=8.7 Hz), 7.00 (2H, dd, J=8.7, 5.5 Hz), 8.01 (1H, s), 8.19 (1H, s).

Production Example 13 Synthesis of (1RS,2SR,5SR)-2-chloromethyl-5-benzyl-2-methyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol (Compound No. I-73 (Compound (I), (R^(a))X^(a)n^(a)=CH₃, (R^(b))X^(b)n^(b)=CH₂Cl, Ym=−(m=0), A=N, isomer type: C))

(1RS,4SR,5RS)-4-Benzyl-1-methyl-5-(1H-1,2,4-triazol-1-ylmethyl)-6-oxabicyclo[3,2,0]heptane (Compound No. (XVI)-5, (Compound (XVI), (R^(a))X^(a)n^(a)=CH₃, Ym=−(m=0), A=N, isomer type: C)) (124.3 mg, 0.439 mmol) was dissolved in DMF (2.5 ml), and heated to 80 degrees C. To this, lithium chloride (223.1 mg, 5.26 mmol) and p-toluenesulfonic acid monohydrate (100.2 mg, 0.526 mmol) were added, and stirring was conducted for 1 hour. After completion of the reaction, the residue was combined with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled away, and the residue was recrystallized from ethyl acetate/hexane to obtain the desired substance.

Product: 92.1 mg

Yield: 65.6%

Description: Colorless crystal, Melting point (m.p.) 94.3 degrees C.

¹H-NMR (CDCl₃) delta:

1.18 (3H, s), 1.40-1.56 (2H, m), 1.67-1.77 (1H, m), 1.91-2.04 (2H, m), 2.34-2.43 (2H, m), 3.22 (1H, d, J=10.8 Hz), 3.57 (1H, d, J=10.8 Hz), 4.02 (1H, s), 4.25 (1H, d, J=14.2 Hz), 4.53 (1H, d, J=14.2 Hz), 7.05 (2H, d, J=7.3 Hz), 7.16 (1H, t, J=7.3 Hz), 7.23 (2H, d, J=7.3 Hz), 8.01 (1H, s), 8.19 (1H, s).

Production Example 14 Synthesis of (1RS,2SR,5SR)-5-(4-chlorobenzyl)-2-chloromethyl-2-methyl-1-imidazol-1-ylmethylcyclopentanol ((Compound No. I-244 (Compound (I), (R^(a))X^(a)n^(a)=CH₃, (R^(b))X^(b)n^(b)=CH₂Cl, Ym=4-Cl, A=CH, isomer type: C))

(1RS,4SR,5RS)-4-(4-Chlorobenzyl)-1-methyl-5-(imidazol-1-ylmethyl)-6-oxabicyclo[3,2,0]heptane (Compound No. (XVI)-6, (Compound (XVI), (R^(a))X^(a)n^(a)=CH₃, Ym=4-Cl, A=CH, isomer type: C)) (100.4 mg, 0.317 mmol) was dissolved in DMF (2 ml), and lithium chloride (201.5 mg, 47.5 mmol) and p-toluenesulfonic acid monohydrate (72.4 mg, 0.380 mmol) were added, and stirring was conducted for 1 hour at 80 degrees C. To this, p-toluenesulfonic acid monohydrate (72.4 mg, 0.380 mmol) was further added and stirring was conducted for further 2 hours. After completion of the reaction, DMF was distilled away under reduced pressure, the residue was combined with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, the solvent was distilled away, and the residue was recrystallized from ethyl acetate/hexane to obtain the desired substance.

Product: 79.0 mg

Yield: 70.3%

Description: White solid, Melting point (m.p.) 186.5 degrees C.

¹H-NMR (400 MHz, CDCl₃) delta:

1.20 (3H, s), 1.39-1.53 (2H, m), 1.70-1.81 (1H, m), 1.85-1.93 (1H, m), 1.93 (1H, dd, J=13.1, 3.3 Hz), 2.26 (1H, dd, J=13.1, 11.2 Hz), 2.34-2.42 (2H, m), 3.39 (1H, d, J=11.0 Hz), 3.57 (1H, d, J=11.0 Hz), 4.07 (1H, d, J=14.5 Hz), 4.31 (1H, d, J=14.5 Hz), 6.98 (2H, d, J=8.3 Hz), 7.08-7.11 (2H, m), 7.21 (2H, d, J=8.3 Hz), 7.64 (1H, s).

Production Example 15 Synthesis of (1RS,2SR,5SR)-2-bromomethyl-5-(4-fluorobenzyl)-2-methyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol (Compound No. I-601 (Compound (I), (R^(a))X^(a)n^(a)=CH₃, (R^(b))X^(b)n^(b)=CH₂Br, Ym=4-F, A=N, isomer type: C))

(1RS, 4SR,5RS)-4-(4-Fluorobenzyl)-1-methyl-5-(1H-1,2,4-triazol-1-ylmethyl)-6-oxabicyclo[3,2,0]heptane (Compound No. (XVI)-4, (Compound (XVI), (R^(a))X^(a)n^(a)=CH₃, Ym=4-F, A=N, isomer type: C)) (79.5 mg, 0.264 mmol) was dissolved in DMF (1.6 ml), lithium bromide (229 mg, 2.64 mmol) and p-toluenesulfonic acid monohydrate (60.2 mg, 0.316 mmol) were added, stirring was conducted for 6.5 hours at room temperature and then for 1.5 hours at 50 degrees C. After completion of the reaction, the residue was combined with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, the solvent was distilled away, and the residue was recrystallized from hexane/ethyl acetate for purification to obtain the desired substance.

Product: 75.1 mg

Yield: 74.4%

Description: White solid, Melting point (m.p.) 130.0 degrees C.

¹H-NMR (CDCl₃) delta:

1.20 (3H, s), 1.42-1.53 (2H, m),1.65-1.76 (1H, m),1.91-1.99 (2H, m),2.30-2.42 (2H, m), 2.95 (1H, d, J=9.9 Hz), 3.54 (1H, d, J=9.9 Hz), 4.08 (1H, s), 4.23 (1H, d, J=14.2 Hz), 4.51 (1H, d, J=14.2 Hz), 6.93 (2H, t, J=8.7 Hz), 7.01 (2H, dd, J=8.7, 5.4 Hz), 8.02 (1H, s), 8.18 (1H, s).

Production Example 16 Synthesis of (1RS,2SR,5SR)-2-bromomethyl-5-benzyl-2-methyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol (Compound No. I-602 (Compound (I), (R^(a))X^(a)n^(a)=CH₃, (R^(b))X^(b)n^(b)=CH₂Br, Ym=−(m=0), A=N, isomer type: C))

(1RS,4SR,5RS)-4-Benzyl-1-methyl-5-(1H-1,2,4-triazol-1-ylmethyl)-6-oxabicyclo[3,2,0]heptane (Compound No. (XVI)-5, (Compound (XVI), (R^(a))X^(a)n^(a)=CH₃, Ym=−(m=0), A=N, isomer type: C)) (50.0 mg, 0.176 mmol) was dissolved in DMF (2 ml), lithium bromide (183.9 mg, 2.12 mmol) and p-toluenesulfonic acid monohydrate (40.3 mg, 0.212 mmol) were added, and stirring was conducted at 50 degrees C. for 1 hour and then at room temperature for 18 hours. After completion of the reaction, the residue was combined with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled away, and the residue was recrystallized from ethyl acetate/hexane to obtain the desired substance.

Product: 28.1 mg

Yield: 43.7%

Description: Colorless crystal, Melting point (m.p.) 103.3 degrees C.

¹H-NMR (CDCl₃) delta:

1.20 (3H, s), 1.45-1.58 (2H, m), 1.67-1.78 (1H, m), 1.93-2.01 (1H, m), 2.03-2.17 (1H, m), 2.35-2.46 (2H, m), 2.92 (1H, d, J=9.9 Hz), 3.54 (1H, d, J=9.9 Hz), 4.05 (1H, s), 4.24 (1H, d, J=14.2 Hz), 4.50 (1H, d, J=14.2 Hz), 7.07 (2H, d, J=7.3 Hz), 7.15 (1H, t, J=7.3 Hz), 7.24 (2H, d, J=7.3 Hz), 8.01 (1H, s), 8.18 (1H, s).

Compounds (I) listed in Table 14 shown below were synthesized by the methods analogous to Production Examples described above.

TABLE 14 Compound No. Description ¹H-NMR (400 MHz, CDCl₃)δ I-97 Colorless 0.94 (3H, t, J = 7.4 Hz), 1.34-1.51 (2H, m), 1.52-1.64 (4H, m), crystal 1.80-1.88 (1H, m), 2.17 (1H, dd, J = 13.0, 11.4 Hz), m.p. 76.5° C. 2.26-2.34 (1H, m), 3.50 (1H, d, J = 11.3 Hz), 4.05 (1H, s), 4.11 (1H, d, J = 11.3 Hz), 4.34 (1H, d, J = 14.1 Hz), 4.79 (1H, d, J = 14.1 Hz), 6.96 (2H, d, J = 7.0 Hz), 7.13 (1H, t, J = 7.3 Hz), 7.18-7.23 (2H, m), 8.01 (1H, s), 8.22 (1H, s). I-86 Colorless 1.18 (3H, s), 1.41-1.57 (2H, m), 1.63-1.74 (1H, m), crystal 1.91-2.10 (2H, m), 2.36-2.47 (2H, m), 3.22 (1H, d, J = 10.8 Hz), 3.59 (1H, m.p. 100.2° C. d, J = 10.8 Hz), 4.29 (1H, d, J = 14.2 Hz), 4.30 (1H, s), 4.56 (1H, d, J = 14.2 Hz), 6.94-6.99 (1H, m), 7.01 (1H, td, J = 7.5, 1.2 Hz), 7.09 (1H, td, J = 7.5, 1.8 Hz), 7.12-7.19 (1H, m), 8.01 (1H, s), 8.20 (1H, s). I-79 White solid 1.19 (3H, s), 1.41-1.52 (2H, m), 1.66-1.76 (1H, m), m.p. 117° C. 1.91-1.99 (2H, m), 2.30-2.41 (2H, m), 3.29 (1H, d, J = 10.8 Hz), 3.58 (1H, d, J = 10.8 Hz), 4.07 (1H, s), 4.27 (1H, d, J = 14.2 Hz), 4.56 (1H, d, J = 14.2 Hz), 7.04-7.10 (4H, m), 8.02 (1H, s), 8.20 (1H, s). I-80 Colorless 1.18 (3H, s), 1.41-1.52 (2H, m), 1.71-1.76 (1H, m), crystal 1.90-2.02 (2H, m), 2.29 (3H, s), 2.31-2.37 (2H, m), 3.20 (1H, d, J = 10.8 Hz), m.p. 138.5° C. 3.57 (1H, d, J = 10.8 Hz), 3.97 (3H, s), 4.24 (1H, d, J = 14.2 Hz), 4.51 (1H, d, J = 14.2 Hz), 6.95 (2H, d, J = 7.9 Hz), 7.05 (2H, d, J = 7.9 Hz), 8.00 (1H, s), 8.18 (1H, s). I-174 White solid 0.81 (3H, s), 1.48-1.55 (1H, m), 1.66-1.96 (3H, m), m.p. 114° C. 2.32-2.54 (3H, m), 3.53 (1H, d, J = 11.1 Hz), 3.63 (1H, d, J = 11.1 Hz), 4.06 (1H, s), 4.26 (1H, d, J = 14.2 Hz), 4.39 (1H, d, J = 14.2 Hz), 6.98 (1H, d, J = 6.9 Hz), 7.10 (1H, brs), 7.13-7.20 (2H, m), 7.99 (1H, s), 8.22 (1H, s). I-374 Colorless 1.24 (3H, s), 1.36-1.45 (1H, m), 1.63-1.69 (1H, m), crystal 1.77-1.20 (1H, m), 2.27-2.37 (2H, m), 3.33 (1H, dd, J = 9.5, 2.3 Hz), 3.57 (1H, d, J = 10.8 Hz), 3.66 (1H, d, J = 10.8 Hz), 4.36 (1H, s), 4.47 (1H, d, J = 14.2 Hz), 4.61 (1H, d, J = 14.2 Hz), 6.92 (1H, dt, J = 6.4, 2.1 Hz), 7.06 (1H, brs), 7.14-7.27 (2H, m), 7.97 (1H, s), 8.21 (1H, s). I-88 White solid 1.18 (3H, s), 1.41-1.47 (2H, m), 1.63-1.69 (1H, m), m.p. 123° C. 1.91-1.99 (2H, m), 2.36-2.39 (2H, m), 3.26 (1H, d, J = 10.8 Hz), 3.58 (1H, d, J = 10.8 Hz), 4.29 (1H, d, J = 14.2 Hz), 4.34 (1H, s), 4.57 (1H, d, J = 14.2 Hz), 6.70-6.78 (2H, m), 7.01-7.07 (1H, m), 8.02 (1H, s), 8.20 (1H, s). I-82 Colorless 1.20 (3H, s), 1.44-1.49 (1H, m), 1.74-1.83 (1H, m), viscous oil 1.93-2.05 (2H, m), 2.37-2.46 (2H, m), 3.24 (1H, d, J = 10.8 Hz), 3.59 (1H, d, J = 10.8 Hz), 4.05 (1H, s), 4.28 (1H, d, J = 14.2 Hz), 4.55 (1H, d, J = 14.2 Hz), 7.13 (2H, d, J = 8.2 Hz), 7.32 (1H, t, J = 7.3 Hz), 7.42 (2H, dd, J = 7.6, 7.3 Hz), 7.47 (2H, d, J = 8.2 Hz), 7.55 (2H, d, J = 7.1 Hz), 8.02 (1H, s), 8.20 (1H, s).

Intermediate compounds (II) employed above are produced as described below.

TABLE 15 Com- pound No. (R^(a1))X^(a1)n^(a1)(L^(a))p^(a4)) (R^(b1))X^(b1)n^(b1)(L^(b))p^(b5)) Ym³⁾ A Type II-1 CH₃ CH₂OTos 4-Cl N C II-2 CH₂OTos CH₃ 4-Cl N C II-3 CH₂CH₂OTos CH₃ 4-Cl N C II-4 CH₂CH₃ CH₂OTos 4-Cl N C II-5 CH₂OMs CH₂OMs 4-Cl N C II-6 CH₂OTos CH₃ 4-Cl N T

The tables can be understood as described below.

4): (R^(a1))X^(a1)n^(a1) (L^(a))p^(a) is indicated as a single substituent. Unless R^(a1) is a hydrogen atom, it should be understood that the hydrogen atom-deficient carbon atom on the left end of (R^(a1))X^(a1)n^(a1) (L^(a))p^(a) serves to the binding to the cyclopentane ring in Compound (II). For example, in Compound No. II-1, (R^(a1))=methyl group, n^(a1)=0, p^(a)=0.

5): (R^(b1))X^(b1)n^(b1) (L^(b))p^(b) is indicated as a single substituent. Unless R^(b1) is a hydrogen atom, it should be understood that the hydrogen atom-deficient carbon atom on the left end of (R^(b1))X^(b1)n^(b1) (L^(b))p^(b) serves to the binding to the cyclopentane ring in Compound (II). For example, in Compound No. II-1, (R^(b1))=methyl group, n^(b2)=0, L^(b)=OTos, p^(b)=1.

3): The number before “-” indicates the binding position when the carbon atom binding to the carbon atom binding to the cyclopentane ring is regarded as being in 1-position in the case of having a substituent on a phenyl ring.

Reference Production Example 1 (1RS,2RS,3SR)-p-toluenesulfonic acid 3-(4-chlorobenzyl)-2-hydroxy-1-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)cyclopentylmethyl ester (Compound No. II-1 (Compound (II), (R^(a1))X^(a1)n^(a1) (L^(a))p^(a)=CH₃, (R^(a1))X^(b1)n^(b1) (L^(b)) p^(b)R^(b1)═CH₂OTos, Ym=4-Cl, A=N, isomer type: C))

Under argon atmosphere, sodium hydride (73 mg (60%, 1.83 mmol) was washed with hexane, and then suspended in dehydrated THF (4 ml) and cooled with ice/water. Then, (1RS,2RS,5SR)-5-(4-chlorobenzyl)-2-hydroxymethyl-2-methyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol (Compound No. VI-1 (Compound (VI), (R^(a2))X^(a2)n^(a2) (OH)P^(a1)==CH₃, (R^(b2))X^(b2)n^(b2) (OH)p^(b1)=CH₂OH, Ym=4-Cl, A=N, isomer type: C))(510 mg, 1.52 mmol) dissolved in dehydrated THF (5 ml) was added dropwise. After returning to room temperature, stirring was conducted for 30 minutes. After cooling with ice/water again, p-toluenesulfonyl chloride (380 mg, 1.97 mmol) was added, and stirring was conducted at the same temperature for 1.5 hours and then at room temperature for 0.5 hour. To the reaction solution, water (20 ml) was added, the reaction was stopped, and then partition with ethyl acetate (100 ml) was conducted. The organic layer was washed with saturated brine (20 ml×3), and then dried over anhydrous sodium sulfate, and then concentrated. Silica gel chromatography (eluent; hexane:ethyl acetate=2:3) was employed for purification to obtain the desired substance.

Product: 0.41 g

Yield: 55%

Description: White solid m.p. 69 degrees C.

¹H-NMR (400 MHz, CDCl₃) delta:

1.09 (3H, s), 1.24-1.30 (1H, m), 1.35-1.45 (1H, m), 1.60-1.80 (3H, m), 2.16-2.32 (2H, m), 3.85 (1H, d, J=9.4 Hz), 3.97 (s, 1H), 3.99 (1H, d, J=9.4 Hz), 4.23 (1H, d, J=14.2 Hz), 4.43 (1H, d, J=14.2 Hz), 6.91 (2H, d, J=8.4 Hz), 7.17 (2H, d, J=8.4 Hz), 7.36 (2H, d, J=8.0 Hz), 7.76 (2H, d, J=8.3 Hz), 7.96 (1H, s), 8.16 (1H, s).

Reference Production Example 2 Synthesis of (1RS,2SR,3RS)-p-toluenesulfonic acid 3-(4-chlorobenzyl)-2-hydroxy-1-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)cyclopentylmethyl ester (Compound No. II-2 (Compound (II), (R^(a1))X^(a1)n^(a1) (L^(a))p^(a)=CH₂OTos, (R^(b1))X^(b1)n^(b1) (L^(b))p^(b)R^(b1)═CH₃, Ym=4-Cl, A=N, isomer type: C))

Under argon atmosphere, (1RS,2SR,5SR)-5-(4-chlorobenzyl)-2-hydroxymethyl-2-methyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol (Compound No. VI-2 (Compound (VI), (R^(a2))X^(a2)n^(a2) (OH)p^(a1)=CH₂OH. (R^(b2))X^(b2)n^(b2) (OH)p^(b1)=CH₃, Ym=4-Cl, A=N, isomer type: C)) (0.205 g, 0.610 mmol) was dissolved in dehydrated THF, and, while cooling with ice, sodium hydride (18 mg, 0.733 mmol) was added, and stirring was conducted for 0.5 hour at room temperature. To this, p-toluenesulfonyl chloride (0.140 g, 0.733 mmol) was added and stirring was conducted at room temperature for 2 hours, and then sodium hydride (12 mg, 0.51 mmol) was added, and stirring was conducted for 2 hours. After completion of the reaction, water (5 ml) and ethyl acetate (25 ml) were added, and partition was conducted. The organic layer was washed with saturated brine (5 ml×3), and then dried over anhydrous sodium sulfate, and then concentrated. Silica gel column chromatography (eluent; hexane:ethyl acetate=1:1) was employed for purification to obtain the desired substance.

Product: 0.21 g

Yield: 69%

Description: White solid

¹H-NMR (400 MHz, CDCl₃) delta:

0.40 (3H, s), 1.27 (1H, m), 1.50-1.71 (3H, m), 2.27 (1H, m), 2.46 (3H, s), 2.65 (2H, d, J=7.4 Hz), 3.64 (1H, d, J=10.2 Hz), 4.01 (1H, d, J=10.2 Hz), 4.21 (1H, d, J=14.2 Hz), 4.44 (1H, d, J=14.2 Hz), 4.84 (1H, s), 7.08 (2H, d, J=8.3 Hz), 7.24 (2H, d, J=8.1 Hz), 7.36 (2H, d, J=8.1 Hz), 7.76 (2H, d, J=8.3 Hz), 7.96 (1H, s), 8.32 (1H, s).

Reference Production Example 3 Synthesis of p-toluenesulfonic acid 2-[(1RS,2SR,3RS)-3-(4-chlorobenzyl)-2-hydroxy-1-methyl-2-(1H-1,2,4-triazol-lylmethyl)cyclopentyl]ethyl ester (Compound No. II-3 (Compound (II), (R^(a1))X^(a1)n^(a1) (L^(a))p^(a)=CH₂CH₂OTos, (R^(b1))X^(b1)n^(b1) (L^(b))p^(b)R^(b1)═CH₃, Ym=4-Cl, A=N, isomer type: C))

(1RS,2SR,5SR)-5-(4-Chlorobenzyl)-2-hydroxyethyl-2-methyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol (Compound No. VI-3 (Compound (VI), (R^(a2))X^(a2)n^(a2) (OH)p^(a1)=CH₂CH₂OH, (R^(b2))X^(b2)n^(b2) (OH)p^(b1)=CH₃, Ym=4-Cl, A=N, isomer type: C)) (32.4 mg, 0.089 mmol) and p-toluenesulfonyl chloride (14.7 mg, 0.085 mmol) were dissolved in THF (1 ml), sodium hydride (60% oil dispersion) (3.1 mg, 0.077 mmol) was added, and stirring was conducted at room temperature for 19 hours. This was stirred for 3.5 hours in an oil bath at 35 degrees C., and then sodium hydride (60% oil dispersion) (0.5 mg, 0.013 mmol) was added, and stirring was conducted further for 30 minutes. After completion of the reaction, the solution was poured into ice/water and extracted with chloroform. The organic layer was washed with an aqueous solution of sodium carbonate and saturated brine, and then dried over sodium sulfate and the solvent was distilled away to obtain a crude intended substance.

Product: 44.3 mg

Yield: 69%

Description: White solid

¹H-NMR (400 MHz, CDCl₃) delta:

0.59 (3H, s), 1.36-1.47 (2H, m), 1.54-1.69 (2H, m), 1.76 (2H, t, J=7.5 Hz), 2.10-2.20 (1H, m), 2.38 (1H, dd, J=13.7, 5.1 Hz), 2.43-2.47 (1H, m), 2.44 (3H, s), 3.94 (1H, s), 4.06-4.22 (3H, m), 4.30 (1H, d, J=12.4 Hz), 6.99 (1H, d, J=8.4 Hz), 7.21 (1H, d, J=8.4 Hz), 7.34 (1H, d, J=8.3 Hz), 7.77 (1H, d, J=8.3 Hz), 7.96 (1H, s), 8.11 (1H, s).

Reference Production Example 4 Synthesis of (1RS,2RS,3SR)-p-toluenesulfonic acid 3-(4-chlorobenzyl)-1-ethyl-2-hydroxy-2-(1H-1,2,4-triazol-1-yl)methylcyclopentylmethyl ester (Compound No. II-4 (Compound (II), (R^(a1))X^(a1)n^(a1) (L^(a))p^(a)=CH₂CH₃, (R^(b1))X^(b1)n^(b1) (L^(b))p^(b)R^(b1)═CH₂OTos, Ym=4-Cl, A=N, isomer type: C))

(1RS,2RS,5SR)-5-(Chlorobenzyl)-2-ethyl-2-hydroxymethyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol (Compound No. VI-4 (Compound (VI), (R^(a2))X^(a2)n^(a2) (OH)p^(a1)=CH₂CH₃, (R^(b2))X^(b2)n^(b2) (OH)p^(b1)=CH₂OH, Ym=4-Cl, A=N, isomer type: C)) (62.3 mg, 0.178 mmol) was dissolved in THF (1 ml), sodium hydride (7.9 mg, 0.198 mmol) was added, and stirring was conducted at room temperature for 30 minutes. This was cooled to −15 degrees C., tosyl chloride (40.8 mg, 0.214 mmol) was added, and stirring was conducted for 1.5 hours while warming to room temperature. After completion of the reaction, water was added and the solution was extracted with ethyl acetate, and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled away, and the residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=2:3) for purification to obtain the desired substance.

Product: 57.6 mg

Yield: 64.2%

Description: White foam

¹H-NMR (400 MHz, CDCl₃) delta:

0.82 (3H, t, J=7.3 Hz), 1.30-1.40 (1H, m), 1.42-1.50 (3H, m), 1.50-1.61 (1H, m), 1.67-1.77 (1H, m), 2.10 (1H, dd, J=14.6, 11.4 Hz), 2.19-2.27 (1H, m), 2.47 (3H, s), 3.91 (1H, d, J=9.5 Hz), 3.97 (1H, s), 4.31 (1H, d, J=14.2 Hz), 4.32 (1H, d, J=9.5 Hz), 4.52 (1H, d, J=14.2 Hz), 6.86 (2H, d, J=8.4 Hz), 7.15 (2H, d, J=8.4 Hz), 7.37 (2H, d, J=8.0 Hz), 7.81 (2H, d, J=8.0 Hz), 7.97 (1H, s), 8.16 (1H, s).

Reference Production Example 5 Synthesis of cis-5-(4-chlorobenzyl)-2,2-bis(methanesulfonyloxymethyl)-1-(1H-1,2,4-triazol-1-yl)methylcyclopentanol (Compound No. II-5 (Compound (II), (R^(a1))X^(a1)n^(a1) (L^(a))p^(a)=CH₂OMs, (R^(b1))X^(b1)n^(b1) (L^(b))p^(b)R^(b1)═CH₂OMs. Ym=4-Cl, A=N, isomer type: C))

cis-5-(4-Chlorobenzyl)-2,2-bis(hydroxymethyl)-1-(1H-1,2,4-triazol-1-yl)methylcyclopentanol (Compound No. VI-5 (Compound (VI), (R^(a2))X^(a2)n^(a2) (OH)p^(a1)=CH₂OH, (R^(b2))X^(b2)n^(b2) (OH)p^(b1)=CH₂OH, Ym=4-Cl, A=N, isomer type: C)) (50.0 mg, 0.142 mmol) was dissolved in THF (1.5 ml), triethylamine (0.0598 ml, 0.426 mmol) was added, and the solution was cooled to 0 degrees C. in an ice bath. To this, methanesulfonyl chloride (0.0246 ml, 0.341 mmol) was added dropwise, and stirring was conducted for 3 hours while warming to room temperature. After completion of the reaction, water was added and extraction with ethyl acetate was conducted. This was washed with a dilute aqueous solution of sodium hydroxide and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled away, and the residue was dried in vacuum to obtain a crude intended substance.

Crude product: 76.9 mg

Crude yield: 107%

Description: Colorless viscous liquid

¹H-NMR (CDCl₃) delta:

1.48-1.58 (1H, m), 1.59-1.73 (2H, m), 1.87-1.96 (1H, m), 2.22-2.34 (2H, m), 2.53 (1H, dd, J=12.7, 9.5 Hz), 2.97 (3H, s), 3.07 (3H, s), 3.92 (1H, d, J=9.9 Hz), 4.15 (1H, d, J=10.4 Hz), 4.20 (1H, d, J=9.9 Hz), 4.25 (1H, d, J=10.4 Hz), 4.28 (1H, d, J=14.3 Hz), 4.54 (1H, d, J=14.3 Hz), 5.18 (1H, s), 7.02 (2H, d, J=8.4 Hz), 7.23 (2H, d, J=8.4 Hz), 8.03 (1H, s), 8.34 (1H, s).

Reference Production Example 6 Synthesis of (1RS,2SR,5RS)-5-(4-chlorobenzyl)-2-(p-toluenesulfonyl)oxymethyl-2-methyl-1-[1,2,4]triazol-1-ylmethylcyclopentanol (Compound No. II-6 (Compound (II), (R^(a1))X^(a1)n^(a1) (L^(a)) p^(a)=CH₂OTos, (R^(b1))X^(b1)n^(b1) (L^(b))p^(b)R^(b1)═CH₃, Ym=4-Cl, A=N, isomer type: T))

(1RS,2SR,5RS)-5-(4-Chlorobenzyl)-2-hydroxymethyl-2-methyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol (Compound No. VI-2 (Compound (VI), (R^(a2))X^(a2)n^(a2) (OH)p^(a1)=CH₂OH, (R^(b2))X^(b2)n^(n2) (OH)p^(b1)=CH₃, Ym=4-Cl, A=N, isomer type: T)) (200 mg, 0.596 mmol) was dissolved in THF (4 ml), sodium hydride (23.8 mg, 0.596 mmol) was added, and stirring was conducted at 50 degrees C. for 40 minutes. To this, while cooling in an ice bath, p-toluenesulfonyl chloride (125 mg, 0.656 mmol) was added and stirring was conducted at room temperature for 1.5 hours. After completion of the reaction, the solvent was distilled away, and water was added and extraction with ethyl acetate was conducted. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate. The solvent was distilled away, and then the residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=1:3) for purification to obtain the desired substance.

Product: 242.8 mg

Yield: 83.2%

Description: Colorless solid

¹H-NMR (CDCl₃) delta:

0.75 (3H, s), 1.21-1.30 (1H, m), 1.49-1.57 (1H, m), 1.63-1.77 (2H, m), 2.18 (1H, t, J=12.8 Hz), 2.38-2.46 (1H, m), 2.46 (3H, s), 2.84 (1H, dd, J=12.8, 3.9 Hz), 3.74 (1H, d, J=10.0 Hz), 3.98 (1H, d, J=10.0 Hz), 4.35 (1H, d, J=14.2 Hz), 4.43 (1H, d, J=14.2 Hz), 4.56 (1H, s), 6.99 (2H, d, J=8.4 Hz), 7.22 (2H, d, J=8.4 Hz), 7.37 (2H, d, J=8.2 Hz), 7.78 (2H, d, J=8.2 Hz), 7.95 (1H, s), 8.28 (1H, s).

The intermediate compounds (VI) employed above can be produced by Reference Production Example 7 described below and analogous methods as well as methods known in references.

Reference Production Example 7 Synthesis of 5-(4-chlorobenzyl)-2-hydroxymethyl-2-methyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol (1) Synthesis of Intermediate 1-(4-chlorobenzyl)-3-methyl-3-hydroxymethyl-2-oxocyclopentane carboxylic acid methyl ester (Compound No. XI-1 (Compound (XI), R¹═CH₃, R²═CH₃, Ym=4-Cl))

To 1-(4-chlorobenzyl)-3-methyl-2-oxocyclopentane carboxylic acid methyl ester (1.12 g, 4.0 mmol), a 37% aqueous solution of formaldehyde (0.90 ml, 12 mmol) and potassium carbonate (276 mg, 2.0 mmol) were added, and vigorous stirring was conducted at room temperature for 4 hours. After completion of the reaction, water was added and, extraction with ethyl acetate (30 ml) was conducted. The organic layer was washed with saturated brine (10 ml), dried over anhydrous sodium sulfate. The solvent was distilled away, and the residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=3:2), and the title compound was obtained as two isomers.

Isomer (a)

Product: 227 mg

Yield: 18%

Description: Colorless oil

¹H-NMR (400 MHz, CDCl₃) delta:

1.10 (3H, s), 1.69 (1H, brdd, J=7.2, 4.6 Hz), 1.72-1.78 (1H, m), 1.84-1.91 (1H, m), 1.91-2.00 (1H, m), 2.39-2.47 (1H, m). 3.00 (1H, d, J=13.9 Hz), 3.20 (1H, d, J=13.9 Hz), 3.25 (1H, dd, J=10.8, 4.6 Hz), 3.45 (1H, dd, J=10.8, 7.2 Hz), 3.73 (3H, s), 7.09 (2H, d, J=8.5 Hz), 7.23 (2H, d, J=8.5 Hz).

Isomer (b)

Product: 953 mg

Yield: 76%

Description: White solid

¹H-NMR (400 MHz, CDCl₃) delta:

0.71 (3H, s), 1.46 (1H, ddd, J=12.9, 7.2, 3.0 Hz), 1.88-1.95 (1H, m),1.92 (1H, brs), 2.04-2.15 (1H, m), 2.38 (1H, ddd, J=13.3, 7.2, 3.0 Hz), 3.14 (2H, s), 3.45 (1H, dd, J=10.9, 5.7 Hz), 3.63 (1H, dd, J=10.9, 6.8 Hz), 3.72 (3H, s), 7.05 (2H, d, J=8.5 Hz), 7.24 (2H, d, J=8.5 Hz).

Similar production methods were employed to synthesize Compounds (XI) listed in Table 16 shown below.

TABLE 16 Compound No. R¹ R² Ym Description ¹H-NMR (400 MHz, CDCl₃)δ XI-2 CH₃ CH₃ 4-F White solid 0.68 (3H, s), 1.45 (1H, ddd, J = 12.7, 7.1, 3.0 Hz), Isomer-(a) 1.88-1.98 (2H, m), 2.04-2.13 (1H, m), 2.38 (1H, ddd, J = 13.2, 7.1, 3.0 Hz), 3.12 (1H, d, J = 13.8 Hz), 3.16 (1H, d, J = 13.8 Hz), 3.45 (1H, dd, J = 11.0, 5.8 Hz), 3.62 (1H, dd, J = 11.0, 6.9 Hz), 3.72 (3H, s), 6.95 (2H, t, J = 8.7 Hz), 7.08 (2H, dd, J = 8.7, 5.4 Hz). XI-2 CH₃ CH₃ 4-F Colorless 1.10 (3H, s), 1.65-1.70 (1H, m), 1.72 (1H, dt, J = 13.3, 7.3 Hz), Isomer-(b) viscous 1.80-1.88 (1H, m), 1.98 (1H, dt, J = 13.6, 7.3 Hz), liquid 2.37-2.45 (1H, m), 3.03 (1H, d, J = 13.9 Hz), 3.18 (1H, d, J = 13.9 Hz), 3.22 (1H, dd, J = 10.8, 4.6 Hz), 3.42 (1H, dd, J = 10.8, 7.3 Hz), 3.73 (3H, s), 6.95 (2H, t, J = 8.7 Hz), 7.12 (2H, dd, J = 8.7, 5.5 Hz). XI-3 CH₃ CH₃ 3-Cl Colorless 0.72 (3H, s), 1.46 (1H, ddd, J = 12.9, 7.1, 3.0 Hz), Isomer-(a) viscous 1.68-1.93 (1H, m), 2.00-2.05 (1H, m), 2.06-2.17 (1H, m), 2.39 (1H, ddd, liquid J = 13.3, 7.1, 3.0 Hz), 3.12 (1H, d, J = 13.7 Hz), 3.16 (1H, d, J = 13.7 Hz), 3.46 (1H, dd, J = 10.9, 5.5 Hz), 3.63 (1H, dd, J = 10.9, 6.7 Hz), 3.72 (3H, s), 6.99 (1H, d, J = 6.2 Hz), 7.11 (1H, s), 7.17-7.23 (2H, m). XI-3 CH₃ CH₃ 3-Cl Colorless 1.10 (3H, s), 1.72-1.79 (2H, m), 1.84-2.04 (2H, m), Isomer-(b) viscous 2.39-2.46 (1H, m), 3.01 (1H, d, J = 13.9 Hz), 3.21 (1H, d, J = 13.9 Hz), liquid 3.25 (1H, dd, J = 10.8, 4.5 Hz), 3.46 (1H, dd, J = 10.8, 7.1 Hz), 3.73 (3H, s), 7.03 (1H, d, J = 6.1 Hz), 7.16 (1H, s), 7.18-7.23 (2H, m). XI-4 CH₃CH₂ CH₃ 4-Cl Colorless 0.75 (3H, t, J = 7.5 Hz), 1.10 (1H, dq, J = 14.5, 7.5 Hz), Isomer-(a) viscous 1.33 (1H, dq, J = 14.5, 7.5 Hz), 1.65-1.71 (1H, m), 1.79-1.86 (1H, liquid m), 1.87-1.98 (2H, m), 2.36-2.43 (1H, m), 3.02 (1H, d, J = 13.8 Hz), 3.20 (1H, d, J = 13.8 Hz), 3.47 (1H, dd, J = 11.0, 4.5 Hz), 3.63 (1H, dd, J = 11.0, 7.3 Hz), 3.71 (3H, s), 7.04 (2H, d, J = 8.5 Hz), 7.23 (2H, d, J = 8.5 Hz). XI-4 CH₃CH₂ CH₃ 4-Cl Colorless 0.81 (3H, t, J = 7.5 Hz), 1.45-1.65 (2H, m), 1.67-1.76 (2H, m), Isomer-(b) viscous 1.85-1.95 (2H, m), 2.37-2.45 (1H, m), 2.99 (1H, d, J = 13.8 Hz), liquid 3.23 (1H, d, J = 13.8 Hz), 3.26 (1H, dd, J = 10.8, 4.0 Hz), 3.51 (1H, dd, J = 10.8, 7.6 Hz), 3-71 (3H, s), 7.07 (2H, d, J = 8.4 Hz), 7.23 (2H, d, J = 8.4 Hz). XI-5 CH₃ CH₃ 2-F Colorless 0.74 (3H, s), 1.50 (1H, ddd, J = 12.9, 7.1, 3.0 Hz), Isomer-(a) viscous 1.85-1.99 (2H, m), 2.03-2.14 (1H, m), 2.38 (1H, ddd, J = 13.5, 7.1, liquid 3.0 Hz), 3.10 (1H, dd, J = 13.8, 1.5 Hz), 3.39 (1H, d, J = 13.8 Hz), 3.46 (1H, dd, J = 11.0, 5.6 Hz), 3.63 (1H, dd, J = 11.0, 6.8 Hz), 3.73 (3H, s), 6.99-7.06 (2H, m), 7.08-7.14 (1H, m), 7.17-7.25 (1H, m). XI-5 CH₃ CH₃ 2-F Colorless 1.11 (3H, s), 1.72-1.80 (1H, m), 1.86-2.01 (3H, m), Isomer-(b) viscous 2.40-2.48 (1H, m), 3.09 (1H, dd, J = 14.0, 1.2 Hz), 3.25 (1H, dd, J = 10.9, liquid 4.5 Hz), 3.33 (1H, dd, J = 14.0, 1.2 Hz), 3.44 (1H, dd, J = 10.9, 7.3 Hz), 3.74 (3H, s), 6.98-7.07 (2H, m), 7.15-7.25 (2H, m). XI-6 CH₃ CH₃ 4-OCF3 Colorless 0.68 (3H, s), 1.43-1.49 (1H, m), 1.88-1.95 (1H, m), Isomer-(a) viscous 1.98-2.01 (1H, m), 2.08-2.16 (1H, m), 2.36-2.42 (1H, m), 3.17 (2H, s), liquid 3.45 (1H, dd, J = 10.9, 5.7 Hz), 3.63 (1H, dd, J = 11.0, 6.8 Hz), 3.72 (3H, s), 7.10-7.16 (4H, m). XI-6 CH₃ CH₃ 4-OCF3 Colorless 1.10 (3H, s), 1.72-1.80 (2H, m), 1.88-2.00 (2H, m), Isomer-(b) viscous 2.38-2.46 (1H, m), 3.02 (1H, d, J = 13.9 Hz), 3.24 (1H, d, J = 13.9 Hz), liquid 3.26 (1H, dd, J = 10.7, 4.6 Hz), 3.47 (1H, dd, J = 10.7, 7.0 Hz), 3.73 (3H, s), 7.10-7.20 (4H, m). XI-7 CH₃ CH₃ 4-CH3 Colorless 0.69 (3H, s), 1.39-1.44 (1H, m), 1.91-1.99 (1H, m), Isomer-(a) viscous 2.03-2.11 (1H, m), 2.15-2.18 (1H, m), 2.30 (3H, s), 2.33-2.39 (1H, m), liquid 3.13 (2H, s), 3.45 (1H, dd, J = 10.9, 5.2 Hz), 3.61 (1H, dd, J = 11.0, 6.5 Hz), 3.71 (3H, s), 6.98 (2H, d, J = 8.0 Hz), 7.05 (2H, d, J = 7.9 Hz). XI-7 CH₃ CH₃ 4-CH3 Colorless 1.09 (3H, s), 1.67-1.83 (3H, m), 1.98-2.05 (1H, m), 2.30 (3H, Isomer-(b) viscous s), 2.31-2.43 (1H, m), 3.05 (1H, d, J = 13.8 Hz), 3.16 (1H, d, liquid J = 13.8 Hz), 3.18 (1H, dd, J = 10.9, 4.9 Hz), 3.38 (1H, dd, J = 10.9, 7.4 Hz), 3.73 (3H, s), 7.02 (2H, d, J = 8.1 Hz), 7.07 (2H, d, J = 8.1 Hz). XI-8 CH₃ CH₃ 2,4-F Colorless 0.76 (3H, s), 1.53 (1H, ddd, J = 12.9, 7.1, 2.9 Hz), Isomer-(a) viscous 1.82-1.90 (1H, m), 1.96 (1H, dd, J = 6.8, 5.7 Hz), 2.08-2.17 (1H, m), liquid 2.42 (1H, ddd, J = 13.5, 7.1, 2.9 Hz), 3.06 (1H, dd, J = 14.0, 1.7 Hz), 3.33 (1H, d, J = 14.0 Hz), 3.46 (1H, dd, J = 10.9, 5.7 Hz), 3.64 (1H, dd, J = 10.9, 6.8 Hz), 3.72 (3H, s), 6.76-6.82 (2H, m), 7.07-7.13 (1H, m). XI-8 CH₃ CH₃ 2,4-F Colorless 1.11 (3H, s), 1.74-1.81 (2H, m), 1.89-1.99 (2H, m), Isomer-(b) viscous 2.41-2.48 (1H, m), 3.04 (1H, d, J = 14.2 Hz), 3.27 (1H, d, J = 14.2 Hz), liquid 3.30 (1H, dd, J = 10.8, 4.5 Hz), 3.48 (1H, dd, J = 10.8, 7.3 Hz), 3.74 (3H, s), 6.75-6.81 (2H, m), 7.16-7.22 (1H, m).

(2) Synthesis of Intermediate 5-(4-chlorobenzyl)-2-methoxymethoxymethyl-2-methylcyclopentanone (Compound (IX), R¹═CH₃, Ym=4-Cl, G=CH₂OCH₃)

1-(4-Chlorobenzyl)-3-methyl-3-hydroxymethyl-2-oxocyclopentane carboxylic acid methyl ester (Compound (XI), R¹═CH₃, R²═CH₃, Ym=4-Cl) (186 mg, 0.60 mmol) was dissolved in methylene chloride (5.6 ml), and dimethoxymethane (2.8 ml) was added. This was cooled in a water bath, diphosphorus pentoxide (372 mg) was added and vigorous stirring was conducted at room temperature for 10 minutes. After completion of the reaction, saturated brine was combined with the reaction solution, and extraction with diethyl ether was conducted. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate. The solvent was distilled away and dried under reduced pressure to obtain a crude 1-(4-chlorobenzyl)-3-methoxymethoxymethyl-3-methyl-2-oxocyclopentane carboxylic acid methyl ester (Compound (X), R¹═CH₃, R²═CH₃, Ym=4-Cl, G=CH₂OCH₂OCH₃) (195 mg). From this, an aliquot (188.8 mg) was dissolved in isopropanol (0.53 ml), a 2M aqueous solution of sodium hydroxide (0.53 ml, 1.12 mmol) was added, and stirring was conducted at 60 degrees C. for 1 hour. After completion of the reaction, water was added and extraction with ethyl acetate was conducted. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate. The solvent was distilled away, and the residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=7:1) to obtain the desired substance as a mixture of two isomers (Isomer (a):Isomer (b)=36:65).

Product: 104.1 mg

Yield: 66%

Description: Colorless oil

¹H-NMR (400 MHz, CDCl₃) delta:

Isomer (a)

1.04 (3H, s), 1.60-1.71 (2H, m), 1.89-1.96 (1H, m), 2.17-2.23 (1H, m), 2.44-2.55 (2H, m), 3.06 (1H, dd, J=13.1, 3.6 Hz), 3.27 (1H, d, J=8.9 Hz), 3.31 (3H, s), 3.52 (1H, d, J=8.9 Hz), 4.51 (1H, d, J=10.1 Hz), 4.52 (1H, d, J=10.1 Hz), 7.10 (2H, d, J=8.4 Hz), 7.24 (2H, d, J=8.4 Hz).

Isomer (b)

0.84 (3H, s), 1.49 (1H, qd, J=12.2, 6.9 Hz), 1.64 (1H, ddd, J=12.7, 6.8, 1.2 Hz), 1.96-2.04 (1H, m), 2.08-2.17 (1H, m), 2.36-2.45 (1H, m). 2.61 (1H, dd, J=14.0, 8.7 Hz), 3.09 (1H, dd, J=14.0, 2.2 Hz), 3.31 (3H, s), 3.32 (1H, d, J=9.1 Hz), 3.62 (1H, d, J=9.1 Hz), 4.53 (1H, d, J=10.8 Hz), 4.54 (1H, d, J=10.8 Hz). 7.09 (2H, d, J=8.5 Hz), 7.23 (2H, d, J=8.5 Hz).

(3) Synthesis of Intermediate 5-(4-chlorobenzyl)-2-methoxymethoxymethyl-2-methyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol (Compound (VII), R¹═CH₃, Ym G=CH₂OCH₃, A=N)

1H-1,2,4-Triazole sodium salt (1.196 g, 13.1 mmol) was dissolved in NMP (7 ml), and heated to an internal temperature of 115 degrees C. To this, 5-(4-chlorobenzyl)-2-methoxymethoxymethyl-2-methylcyclopentanone (Compound (IX), R¹═CH₃, Ym=4-Cl, G=CH₂OCH₃) (2.60 g, 8.76 mmol) was added, and washed thoroughly with NMP (1.8 ml). After the internal temperature became 115 degrees C. again, sodium t-butoxide (505 mg, 5.26 mmol) and trimethylsulfoxonium bromide (2.2379 g, 1.476 mmol) were added in portions over about 3 hours. After completion of the addition, stirring was conducted at the same temperature for 75 minutes. The reaction solution was cooled to 35 degrees C., and then, to the reaction solution, water was added and extraction with ethyl acetate was conducted. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled away and the residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=3:1 to 0:1) for purification to obtain the desired substance.

Product: 2.36 g

Yield: 71%

Description: Colorless viscous oil

(4) Synthesis of 5-(4-chlorobenzyl)-2-hydroxymethyl-2-methyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol (Compound (VI-a)-1, R¹═CH₃, Ym=4-Cl, A=N)

5-(4-Chlorobenzyl)-2-methoxymethoxymethyl-2-methyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol (Compound (VII), R¹═CH₃, Ym=4-Cl, G=CH₂OCH₃, A=N) (629 mg, 1.66 mmol) was dissolved in methanol (6.3 ml), 10% hydrogen chloride-methanol (6.3 ml, 1.73 mmol) was added and stirring was conducted at room temperature for 48 hours. After completion of the reaction, the solvent was distilled away, and water was added. After ethyl acetate (80 ml) was added, an aqueous solution of sodium hydroxide was added until the pH became 10. The organic layer was separated, washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled away to obtain the title compound (VI-1 (Compound (VI), (R^(a2))X^(a2)n^(a2) (OH)p^(a1)=CH₃, (R^(b2))X^(b2)n^(b2) (OH)p^(b1)=CH₂OH, Ym=4-Cl, A=N, isomer type: C): VI-2 (Compound (VI), (R^(a2))X^(a2)n^(a2) (OH)p^(a1)=CH₂OH, (R^(b2))X^(b2)n^(b2) (OH)p^(b1)=CH₃, Ym=4-Cl, A=N, isomer type: C): other isomers (isomer type: T)=6:3:1).

Yield: 498 mg

Yield: 89.5%

Description: White solid

By the methods of Reference Production Example described above and the like, the following Compounds (VI) were synthesized.

TABLE 17 Compound No. (R^(a2))X^(a2)n^(a2)(OH)p^(a16)) (R^(b2))X^(b2)n^(b2)(OH)p^(b17)) Ym³⁾ A Type VI-1 CH₃ CH₂OH 4-Cl N C VI-2 CH₂OH CH₃ 4-Cl N C VI-3 CH₂CH₂OH CH₃ 4-Cl N C VI-4 CH₂CH₃ CH₂OH 4-Cl N C VI-5 CH₂OH CH₂OH 4-Cl N C VI-6 CH₂OH CH₃ 4-Cl N T

The tables can be understood as described below.

6): (R^(a2))X^(a2)n^(a2) (OH)p^(a1) is indicated as a single substituent. Unless R^(a) is a hydrogen atom, it should be understood that the hydrogen atom-deficient carbon atom on the left end of (R^(a2))X^(a2)n^(a2) (OH)p^(a1) serves to the binding to the cyclopentane ring in Compound (VI). For example, in Compound No. VI-1, (R^(a2))=methyl group, n^(a2)=0, p^(a1)=0.

7): (R^(b2))X^(b2)n^(b2) (OH)p^(b1) is indicated as a single substituent. Unless R^(b) is a hydrogen atom, it should be understood that the hydrogen atom-deficient carbon atom on the left end of (R^(b2))X^(b2)n^(b2) (OH)p^(b1) serves to the binding to the cyclopentane ring in Compound (VI). For example, in Compound No. VI-1, (R^(b2))=methyl group, n^(b2)=0, p^(b1)=1.

3): “-” indicates a non-substitution (m=0). The number before “-” indicates the binding position when the carbon atom binding to the carbon atom binding to the cyclopentane ring is regarded as being in 1-position in the case of having a substituent on a phenyl ring.

TABLE 18 Compound No. Description ¹H-NMR (400 MHz, CDCl₃)δ VI-3 Colorless 0.84 (3H, s), 1.45-1.62 (4H, m), 1.63-1.71 (1H, m), 1.77 (1H, viscous oil dt, J = 13.6, 7.9 Hz), 1.97-2.03 (1H, m), 2.12-2.21 (1H, m), 2.42 (1H, dd, J = 13.6, 10.1 Hz), 2.46 (1H, dt, J = 13.6, 5.6 Hz), 3.67-3.86 (2H, m), 4.12 (1H, d, J = 13.9 Hz), 4.0 (1H, s), 4.50 (1H, d, J = 13.9 Hz), 6.92 (2H, d, J = 8.5 Hz), 7.18 (2H, d, J = 8.4 Hz), 7.96 (1H, s), 8.19 (1H, s). VI-4 Colorless 0.88 (3H, t, J = 7.4 Hz), 1.27-1.36 (1H, m), 1.41-1.52 (2H, m), viscous oil 1.54-1.66 (2H, m), 1.70-1.82 (1H, m), 1.82-1.93 (1H, m), 2.03-2.17 (2H, m), 2.34-2.41 (1H, m), 3.28 (1H, d, J = 11.1 Hz), 3.72 (1H, d, J = 11.1 Hz), 4.24 (1H, d, J = 14.1 Hz), 4.45 (1H, d, J = 14.1 Hz), 5.03 (1H, brs), 6.97 (2H, d, J = 8.4 Hz), 7.20 (2H, d, J = 8.4 Hz), 7.96 (1H, s), 8.26 (1H, s). VI-5 White solid 1.20-1.25 (1H, m), 1.43-1.61 (5H, m), 2.05-2.15 (2H, m), 2.40-2.48 (1H, m), 3.63 (1H, d, J = 11.1 Hz), 3.75 (1H, d, J = 14.0 Hz), 3.77 (1H, d, J = 14.0 Hz), 3.86 (1H, d, J = 11.1 Hz), 4.45 (1H, d, J = 14.3 Hz), 4.75 (1H, d, J = 14.3 Hz), 4.84 (1H, brs), 6.97 (2H, d, J = 8.4 Hz), 7.20 (2H, d, J = 8.4 Hz), 8.00 (1H, s), 8.24 (1H, s). VI-6 White solid 1.01 (3H, s), 1.28-1.38 (1H, m), 1.50-1.65 (2H, m), 1.73-1.83 (1H, m), 2.08 (1H, t, J = 5.0 Hz), 2.18 (1H, t, J = 12.7 Hz), 2.37-2.46 (1H, m), 2.76 (1H, dd, J = 12.7, 3.3 Hz), 3.45 (1H, dd, J = 11.2, 5.0 Hz), 3.74 (1H, dd, J = 11.2, 5.1 Hz), 3.97 (1H, s), 4.47 (1H, d, J = 14.3 Hz), 4.58 (1H, d, J = 14.3 Hz), 7.02 (2H, d, J = 8.4 Hz), 7.22 (2H, d, J = 8.4 Hz), 7.97 (1H, s), 8.30 (1H, s).

¹H-NMR Spectra of Compounds VI-1 and VI-2 were well in agreement with the description in JPA5-271197.

Some of the intermediate compounds (V) are produced as described below.

Reference Production Example 8 Synthesis of 2-(2-chloro-2-propenyl)-5-(4-chlorobenzyl)-2-methylcyclopentanone (Compound (V), (R^(a))X^(a)n^(a)=CH₃, (R^(b))X^(b)n^(b)=CH₂CCl═CH₂) (1) Synthesis of Intermediate 3-(2-chloro-2-propenyl)-1-(4-chlorobenzyl)-3-methyl-2-oxocyclopentane carboxylic acid methyl ester (Compound (XIII), R¹═CH₃, (R^(b))X^(b)n^(b)=CH₂CCl═CH₂, R²═CH₃)

1-(4-chlorobenzyl)-3-methyl-2-oxocyclopentane carboxylic acid methyl ester (Compound (XII), R¹═CH₃, R²═CH₃) (4.0 g, 14.2 mmol) was dissolved in DMF (20 ml), sodium hydride (0.63 g (ca. 60% in mineral oil), 15.8 mmol) was added, and the solution was heated to about 60 degrees C., and then cooled with ice. 2,3-Cichloropropene (1.89 g, 17.0 mmol) was added, the ice bath was removed, stirring was conducted at room temperature for 5 hours, and then stirring was conducted at about 60 degrees C. for 1 hour. To the reaction solution, water (50 ml) was added, extraction with ethyl acetate (80 ml×2) was conducted, and then the organic layer was washed with saturated brine (50 ml), and then dried over anhydrous sodium sulfate, and concentrated. A silica gel column (eluent; hexane:ethyl acetate=10:1) was employed for purification to obtain the desired substance.

Product: 2.94 g

Yield: 58%

Description: Colorless oil

¹H-NMR (400 MHz, CDCl₃) delta:

0.67 (2.52H, s), 1.24 (0.48H, s), 1.62-1.72 (0.84; H. m), 1.78-2.00 (1.16; H. m), 2.10-2.23 (1H, m). 2.30-2.40 (1H, m), 2.40-2.51 (0.32H, m), 2.51 (0.84H, d, J=14.4 Hz), 2.58 (0.84H, d, J=14.4 Hz), 2.94 (0.16H, d, J=13.8 Hz), 3.14 (0.84H, d, J=13.8 Hz), 3.18 (0.84H, d, J=13.8 Hz), 3.23 (0.16H, d, J=13.8 Hz), 3.71 (2.52H, s), 3.71 (0.48H, s), 5.08-5.10 (0.16H, m), 5.12-5.14 (0.84H, m), 5.23-5.25 (0.84H, m), 5.25-5.27 (0.16H, m), 7.03-7.10 (2H. m), 7.20-7.26 (2H, m).

(2) Synthesis of 2-(2-chloro-2-propenyl)-5-(4-chlorobenzyl)-2-methylcyclopentanone (Compound (V), (R^(a))X^(a)n^(a)=CH₃, (R^(b))X^(b)n^(b)=CH₂CCl═CH₂)

3-(2-Chloro-2-propenyl)-1-(4-chlorobenzyl)-3-methyl-2-oxocyclopentane carboxylic acid methyl ester (Compound (XIII), R¹=(R^(b))X^(b)n^(b)=CH₂CCl═CH₂, R²═CH₃) (2.90 g, 8.16 mmol) was dissolved in i-PrOH (5 ml), and then an aqueous solution of NaOH (0.65 g, 16.3 mmol) dissolved in water (5.4 ml) was added, and stirring under reflux was conducted for 2.5 hours. Water (50 ml) was added, and extraction with hexane (50 ml×2) was conducted. The organic layer was dried over anhydrous sodium sulfate, and concentrated to obtain the desired substance

Product: 1.96 g

Yield: 81%

Description: Colorless oil

¹H-NMR (400 MHz, CDCl₃) delta:

0.85 (1.98H, s), 1.10 (1.02H, s), 1.42-1.82 (2H, m), 1.90-2.07 (1.66H, m), 2.15-2.25 (0.34H, m), 2.32-2.70 (4H, m), 3.02-3.17 (1H, m), 5.13 (0.34H, s), 5.13-5.16 (0.66H, 5.24 (0.66H, s), 5.25-5.28 (0.34H, m), 7.06-7.13 (2H, m), 7.20-7.27 (2H, m).

The intermediate compounds (XVI) are produced also as described below.

TABLE 19 Compound No. (R^(a))X^(a)n^(a1)) Ym³⁾ A Type XVI-1 CH₃ 4-Cl N C XVI-2 CH₃ 4-Cl N T XVI-3 CH₃ 3-Cl N C XVI-4 CH₃ 4-F N C XVI-5 CH₃ — N C XVI-6 CH₃ 4-Cl CH C XVI-7 CH₃CH₂ 4-Cl N C XVI-8 CH₃CH₂ — N C XVI-9 CH₃ 2-F N C XVI-10 CH₃ 4-OCF₃ N C XVI-11 CH₃ 4-CH₃ N C XVI-12 CH₃ 3-Cl N T XVI-13 CH₃ 2,4-F N C XVI-14 CH₃ 4-Ph N C

The tables can be understood as described below.

8): (R^(a))X^(a)n^(a) is indicated as a single substituent. Unless R^(a) is a hydrogen atom, it should be understood that the hydrogen atom-deficient carbon atom on the left end of (R^(a))X^(a)n^(a) serves to the binding to the cyclopentane ring in Compound (XVI). For example, in Compound No. XVI-1, (R^(a))=methyl group, n^(a)=0.

3): “-” indicates a non-substitution (m=0). The number before “-” indicates the binding position when the carbon atom binding to the carbon atom binding to the cyclopentane ring is regarded as being in 1-position in the case of having a substituent on a phenyl ring.

Reference Production Example 9 Synthesis of (1RS,4SR,5RS)-4-(4-chlorobenzyl)-1-methyl-5-(1H-1,2,4-triazol-1-ylmethyl)-6-oxabicyclo[3,2,0]heptane (Compound No. XVI-1 (Compound (XVI), (R^(a))X^(a)n^(a)=CH₃, Ym=4-Cl, A=N, isomer type: C) and

(1RS,4RS,5RS)-4-(4-chlorobenzyl)-1-methyl-5-(1H-1,2,4-triazol-1-ylmethyl)-6-oxabicyclo[3,2,0]heptane (Compound No. (XVI-2) (Compound No. (XVI), (R^(a))X^(a)n^(a)=CH₃, Ym=4-Cl, A=N, isomer type: T)

Sodium hydride (3.82 g, 95.5 mmol) washed with hexane, and suspended in THF (50 ml). This was cooled in an ice bath, and the isomer mixture of 5-(4-chlorobenzyl)-2-hydroxyethylmethyl-2-methyl-1-[1,2,4]triazol-1-ylmethylcyclopentanol (Compound No. (VI-a), R¹═CH₃, Ym=4-Cl, A=N) (26.1 g, 77.7 mmol) was dissolved in THF (185 ml), and added dropwise over 30 minutes.

After completion of the dropwise addition, stirring was conducted while returning to room temperature for 40 minutes, and then the solution was cooled again in the ice bath and p-toluenesulfonyl chloride (13.2 g, 69.3 mmol) was added and stirring was conducted for 70 minutes. To this, sodium hydride (4.13 g, 103 mmol) was added over 5 minutes and stirring was conducted at room temperature for 1 hour. After completion of the reaction, the content was poured into ice/water, and extracted with ethyl acetate. After washing with saturated brine and drying over anhydrous sodium sulfate, the solvent was distilled away. The resultant residue was recrystallized with ethyl acetate/hexane, and a solid fraction was recovered by filtration. The mother liquor was concentrated, and the resultant residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=1:3 to 0:1) for purification to obtain the desired substance.

Compound No. (XVI-1)

Product: 17.26 g

Yield: 70.0%

Description: White solid, Melting point (m.p.) 95-96 degrees C.

¹H-NMR (CDCl₃) delta:

1.21 (3H, s), 1.38-1.39 (1H, m), 1.69-1.80 (2H, m), 1.81-1.91 (2H, m), 2.31 (1H, dd, J=13.5, 4.0 Hz), 2.50 (1H, dd, J=13.5, 9.3 Hz), 4.22 (2H, s), 4.43 (1H, d, J=15.0 Hz), 4.48 (1H, d, J=15.0 Hz), 7.04 (1H, d, J=8.4 Hz), 7.22 (1H, d, J=8.4 Hz), 7.95 (1H, s), 8.15 (1H, s).

Compound No. (XVI-2)

Product: 2.57 g

Yield: 10.4%

Description: White solid, Melting point (m.p.) 94.5 degrees C.

¹H-NMR (CDCl₃) delta:

1.28 (3H, s), 1.56 (1H, dd, J=13.1, 6.5 Hz), 1.73 (1H. tdd. J=13.2, 6.6, 1.6 Hz), 1.85 (1H, dd, J=13.1, 6.8 Hz), 1.97-2.17 (3H, m), 3.04 (1H, d, J=11.1 Hz), 4.16 (1H, d, J=6.0 Hz), 4.35 (1H, dd, J=6.0, 1.6 Hz), 4.56 (1H, d, J=14.6 Hz), 4.74 (1H, d, J=14.6 Hz), 6.94 (2H, d, J=8.3 Hz), 7.22 (2H, d, J=8.3 Hz), 7.97 (1H, s), 8.33 (1H, s).

Similar methods were employed to synthesis Compounds (XVI) listed in Table 19 shown above. Respective MNR spectra are shown below.

TABLE 20 Compound No. Description ¹H-NMR (400 MHz, CDCl₃) δ XVI-3 Colorless 1.20 (3H, s), 1.22-1.35 (1H, m), 1.61-1.82 (2H, m), viscous oil 1.84-1.89 (2H, m), 2.31 (1H, dd, J = 13.6, 4.0 Hz), 2.51 (1H, dd, J = 13.5, 9.4 Hz), 4.23 (2H, s), 4.43 (1H, d, J = 15.0 Hz), 4.48 (1H, d, J = 15.0 Hz), 6.99 (1H, d, J = 6.7 Hz), 7.13 (1H, s), 7.14-7.21 (2H, m), 7.96 (1H, s), 8.16 (1H, s). XVI-4 White solid 1.20 (3H, s), 1.23-1.35 (1H, m), 1.61-1.80 (2H, m), m.p. 88.0-88.7° C. 1.82-1.90 (2H, m), 2.31 (1H, dd, J = 13.5, 4.0 Hz), 2.50 (1H, dd, J = 13.5, 9.2 Hz), 4.21 (1H, d, J = 7.9 Hz), 4.23 (1H, d, J = 7.9 Hz), 4.42 (1H, d, J = 14.9 Hz), 4.47 (1H, d, J = 14.9 Hz), 6.94 (2H, t, J = 8.8 Hz), 7.07 (1H, dd, J = 8.8, 5.5 Hz), 7.95 (1H, s), 8.14 (1H, s). XVI-5 White solid 1.20 (3H, s), 1.27-1.37 (1H, m), 1.67-1.79 (2H, m), m.p. 66.6-68.3° C. 1.79-1.95 (2H, m), 2.44 (1H, dd, J = 13.5, 4.7 Hz), 2.56 (1H, dd, J = 13.5, 8.5 Hz), 4.20 (1H, dd, J = 6.0, 1.3 Hz), 4.23 (1H, d, J = 6.0 Hz), 4.37 (1H, d, J = 14.9 Hz), 4.45 (1H, d, J = 14.9 Hz), 7.12 (2H, d, J = 7.3 Hz), 7.18 (1H, t, J = 7.3 Hz), 7.25 (2H, t, J = 7.3 Hz), 7.93 (1H, s), 8.02 (1H, s). XVI-6 Colorless 1.12 (3H, s), 1.22-1.34 (1H, m), 1.67-1.78 (2H, m), viscous oil 1.78-1.90 (2H, m), 1.97-2.06 (1H, m), 2.15 (1H, dd, J = 13.7, 3.9 Hz), 2.51 (1H, dd, J = 13.7, 9.7 Hz), 4.15 (1H, d, J = 15.1 Hz), 4.20 (1H, d, J = 6.0 Hz), 4.22 (1H, dd, J = 15.1 Hz), 4.22 (1H, dd, J = 6.0, 1.2 Hz), 7.02 (2H, d, J = 8.4 Hz), 7.09 (2H, d, J = 1.0 Hz), 7.21 (2H, d, J = 8.4 Hz), 7.59 (1H, s). XVI-7 White solid 0.77 (3H, t, J = 7.4 Hz), 1.19-1.28 (1H, m), 1.47-1.58 (1H, m), m.p. 71.4-73.9° C. 1.68-1.87 (5H, m), 2.27 (1H, dd, J = 13.4, 3.6 Hz), 2.47 (1H, dd, J = 13.4, 9.3 Hz), 4.20 (1H, d, J = 6.1 Hz), 4.30 (1H, dd, J = 6.1, 1.4 Hz), 4.45 (1H, d, J = 14.9 Hz), 4.49 (1H, d, J = 14.9 Hz), 7.04 (1H, d, J = 8.4 Hz), 7.22 (1H, d, J = 8.4 Hz), 7.95 (1H, s), 8.15 (1H, s). XVI-8 White solid 0.77 (3H, t, J = 7.4 Hz), 1.20-1.29 (1H, m), 1.49-1.60 (1H, m), m.p. 51.4-54.5° C. 1.67-1.90 (5H, m), 2.40 (1H, dd, J = 13.4, 4.1 Hz), 2.54 (1H, dd, J = 13.4, 8.4 Hz), 4.20 (1H, d, J = 6.1 Hz), 4.28 (1H, dd, J = 6.1, 1.3 Hz), 4.39 (1H, d, J = 14.9 Hz), 4.47 (1H, d, J = 14.9 Hz), 7.12 (2H, d, J = 6.9 Hz), 7.14-7.20 (1H, m), 7.24-7.29 (2H, m), 7.93 (1H, s), 8.03 (1H, s). XVI-9 White solid 1.18 (3H, s), 1.28-1.37 (1H, m), 1.67-1.77 (2H, m), m.p. 54.9-57.4° C. 1.83-1.96 (2H, m), 2.47 (1H, dd, J = 13.6, 3.9 Hz), 2.65 (1H, dd, J = 13.6, 8.7 Hz), 4.19 (1H, dd, J = 6.0, 1.3 Hz), 4.23 (1H, d, J = 6.0 Hz), 4.40 (1H, d, J = 15.0 Hz), 4.49 (1H, d, J = 15.0 Hz), 6.95-7.02 (1H, m), 7.02-7.07 (1H, m), 7.14-7.21 (2H, m), 7.94 (1H, s), 8.14 (1H, s). XVI-10 Colorless 1.22 (3H, s), 1.24-1.34 (1H, m), 1.69-1.75 (2H, m), viscous oil 1.79-1.87 (2H, m), 2.32 (1H, dd, J = 13.6, 3.8 Hz), 2.52 (1H, dd, J = 13.5, 9.6 Hz), 4.24 (2H, s), 4.45 (1H, d, J = 14.9 Hz), 4.50 (1H, d, J = 14.9 Hz), 7.09-7.15 (4H, m), 7.95 (1H, s), 8.16 (1H, s). XVI-11 White solid 1.19 (3H, s), 1.26-1.34 (1H, m), 1.69-1.90 (4H, m), 2.31 (3H, s), 2.42 (1H, dd, J = 13.5, 4.6 Hz), 2.53 (1H, dd, J = 13.5, 8.5 Hz), 4.18 (1H, dd, J = 6.0, 1.3 Hz), 4.22 (1H, d, J = 6.0 Hz), 4.36 (1H, d, J = 15.0 Hz), 7.01 (2H, d, J = 7.9 Hz), 7.07 (2H, d, J = 7.9 Hz), 7.92 (1H, s), 8.02 (1H, s). XVI-12 Colorless 1.28 (3H, s), 1.52-1.59 (1H, m), 1.70-1.78 (1H, m), viscous oil 1.83-1.91 (2H, m), 2.03-2.17 (2H, m), 3.08 (1H, d, J = 9.8 Hz), 4.16 (1H, d, J = 6.1 Hz), 4.35 (1H, dd, J = 6.1, 1.7 Hz), 4.56 (1H, d, J = 14.6 Hz), 4.74 (1H, d, J = 14.6 Hz), 6.89-6.91 (1H, m), 7.03 (1H, brs), 7.15-7.21 (2H, m), 7.98 (1H, s), 8.33 (1H, s). XVI-13 Colorless 1.19 (3H, s), 1.24-1.33 (1H, m), 1.67-1.74 (2H, m), viscous oil 1.86-1.88 (2H, m), 2.35 (1H, d, J = 13.3 Hz), 2.60 (1H, dd, J = 13.5, 8.9 Hz), 4.21 (1H, dd, J = 6.0, 1.2 Hz), 4.23 (1H, d, J = 6.0 Hz), 4.45 (1H, d, J = 15.0 Hz), 4.50 (1H, d, J = 15.0 Hz), 6.72-6.80 (2H, m), 7.08-7.14 (1H, m), 7.95 (1H, s), 8.22 (1H, s). XVI-14 Colorless 1.22 (3H, s), 1.31-1.38 (1H, m), 1.72-1.76 (1H, m), viscous oil 1.80-1.94 (3H, m), 2.46 (1H, dd, J = 13.6, 4.5 Hz), 2.61 (1H, dd, J = 13.6, 8.3 Hz), 4.23 (1H, dd, J = 6.2, 1.0 Hz), 4.26 (1H, d, J = 6.2 Hz), 4.43 (1H, d, J = 14.9 Hz), 4.50 (1H, d, J = 14.9 Hz), 7.21 (2H, d, J = 8.2 Hz), 7.33 (1H, t, J = 7.3 Hz), 7.43 (2H, dd, J = 7.9, 7.3 Hz), 7.51 (2H, d, J = 8.2 Hz), 7.58 (2H, d, J = 8.1 Hz), 7.96 (1H, s), 8.11 (1H, s).

The intermediate (XXI) for producing Compound No. I-1 can otherwise be synthesized according to the method described in Reference Production Example 10 described below.

Reference Production Example 10 Synthesis of (1RS,4SR,5RS)-4-(4-chlorobenzyl)-1-methyl-5-(1H-1,2,4-triazol-1-ylmethyl)-6-oxobicyclo[3,2,0]heptane (Compound (XXI), Ym=4-Cl, A=N, isomer type: C) cis-5-(4-Chlorobenzyl)-2,2-bis

(hydroxymethyl)-1-(1H-1,2,4-triazol-1-yl)methylcyclopentanol (Compound No. VI-5 (Compound (VI), (R^(a2))X^(a2)n^(a2) (OH)p^(a1)=CH₂OH, (R^(b2))X^(b2)n^(b2) (OH)p^(b1)=CH₂OH, Ym=4-Cl, A=N, isomer type: C)) (15 mg, 0.046 mmol) was dissolved in DME (0.8 ml), sodium hydride (4.4 mg, 0.11 mmol) was added, and stifling was conducted at room temperature for 5 minutes. To this solution, p-toluenesulfonyl chloride (9.1 mg, 0.048 mmol) was added, and stirring was conducted at room temperature for 0.4 hour, and then sodium hydride (9.0 mg, 0.23 mmol) and p-toluenesulfonyl chloride (4.0 mg, 0.021 mmol) were further added and stirring was conducted for 0.4 hour to obtain toluene-4-sulfonic acid 4-(4-chlorobenzyl)-5-[1,2,4]triazol-1-ylmethyl-6-oxabicyclo[3,2,0]hepta-1-ylmethyl ester (Compound No. XX-1 (Compound (XX), Ym=4-Cl, A=N) as an intermediate. This was combined with sodium iodide (34 mg, 0.23 mmol) and zinc powder (29 mg, 0.44 mmol) and heated under reflux for 0.6 hour. After completion of the reaction, the solution was cooled to room temperature, the remaining solid was removed by filtration, and the residue was combined with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled away, and the resultant residue was purified by silica gel chromatography (eluent; hexane:ethyl acetate=1:1 to 1:5) to obtain the desired substance.

Product: 3.2 mg (0.010 mmol)

Yield: 22%

This Compound (XXI) has a meaning identical to the abovementioned Compound (XVI)-1 and the NMR spectra were in complete agreement.

The intermediate (XIX) employed here can be synthesized in accordance with Reference Production Example 11 described below.

Reference Production Example 11 (1) Synthesis of 1-(4-chlorobenzyl)-3,3-bis-hydroxymethyl-2-oxo-cyclopentancarboxylic acid methyl ester (Compound (XXVI), R²═CH₃, Ym=4-Cl)

1-(4-Chlorobenzyl)-2-oxo-cyclopentancarboxylic acid methyl ester (Compound No. (XXV)-1, (Compound (XXV), R²═CH₃, Ym=4-Cl, A=N) (266.7 mg, 1.00 mmol) was combined with potassium carbonate (69 mg, 0.50 mmol), 37% aqueous solution of formaldehyde (0.242 ml, 3.00 mmol) and THF (0.72 ml) and vigorous stirring was conducted at room temperature for 5 hours. After completion of the reaction, water was added and extraction with ethyl acetate was conducted. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate and the solvent was distilled away. The residue was subjected to silica gel column chromatography (eluent; ethyl acetate:hexane=2:1) for purification to obtain the desired substance.

Product: 305.8 mg

Yield: 93.6%

Description: Colorless viscous liquid

¹H-NMR (400 MHz, CDCl₃) delta:

1.72-1.80 (1H, m), 1.91-2.01 (3H, 2.15-2.19 (1H, 2.40-2.45 (1H, m), 3.10 (1H, d, J=13.8 Hz), 3.17 (1H, d, J=13.8 Hz), 3.36 (1H, dd, J=11.0, 7.3 Hz), 3.43 (1H, dd, J=11.0, 4.2 Hz), 3.69-3.75 (2H, m), 3.73 (3H. s), 7.05 (2H, d, J=8.4 Hz), 7.24 (2H, d, J=8.4 Hz).

(2) Synthesis of 1-(4-chlorobenzyl)-3,3-bis-methoxymethoxymethyl-2-oxo-cyclopentancarboxylic acid methyl ester (Compound (XXVII), G²=CH₂OCH₃, R²═CH₃, Ym=4-Cl)

1-(4-Chlorobenzyl)-3,3-bis-hydroxymethyl-2-oxo-cyclopentancarboxylic acid methyl ester (Compound (XXVI), R²═CH₃, Ym=4-Cl) (3.6871 g, 10.0 mmol) was dissolved in chloroform (14.5 ml), combined with dimethoxymethane (14.5 ml), lithium bromide (173.6 mg, 2.00 mmol) and p-toluenesulfonic acid monohydrate (190.2 mg, 1.00 mmol) and stirring was conducted at room temperature for 2 hours. After completion of the reaction, an aqueous solution of sodium hydrogen carbonate and diethyl ether were added, and the organic layer was separated. This was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled away, and the residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=2:1 to 1:1) for purification to obtain the desired substance.

Product: 2.3455 g

Yield: 56.5%

Description: Colorless viscous liquid

¹H-NMR (400 MHz, CDCl₃) delta:

1.85-1.93 (1H, m), 2.00-2.08 (1H, m), 2.14-2.22 (1H, m), 2.43-2.51 (1H, m), 2.88 (1H, d, J=13.8 Hz), 3.28 (3H, s), 3.29 (3H, m), 3.28-3.32 (1H, m), 3.38 (1H, dd, J=9.1, 6.1 Hz), 3.53 (1H, dd, J=9.1, 6.1 Hz), 4.46 (1H, d, J=6.5 Hz), 4.49 (2H, s), 4.49 (1H, d, J=6.5 Hz), 7.06 (2H, d, J=8.4 Hz), 7.22 (2H, d, J=8.4 Hz).

(3) Synthesis of 5-chlorobenzyl-2,2-bis-methoxymethoxymethyl-cyclopentanone (Compound (XXII), G²=CH₂OCH₃, Ym=4-Cl)

1-(4-Chlorobenzyl)-3,3-bis-methoxymethoxymethyl-2-oxo-cyclopentancarboxylic acid methyl ester (Compound (XXVII), G²=CH₂OCH₃, R²═CH₃, Ym=4-Cl) (2.2895 g, 5.52 mmol) was dissolved in isopropanol (5.5 ml), a 2 mol/l aqueous solution of sodium hydroxide (5.5 ml) was added and stirring was conducted for 2 hours at 90 degrees C. After completion of the reaction, water was added and extraction with ethyl acetate was conducted. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled away, and the residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=3:1) for purification to obtain the desired substance.

Product: 1.3029 g

Yield: 66.1%

Description: Colorless viscous liquid

¹H-NMR (400 MHz, CDCl₃) delta:

1.57-1.67 (1H, m), 1.96-2.11 (3H, m), 2.40-2.49 (1H, m), 2.52 (1H, dd, J=13.5, 9.3 Hz), 3.11 (1H, dd, J=13.5, 4.2 Hz), 3.30 (6H, s), 3.35 (1H, d, J=9.1 Hz), 3.42 (1H, d, J=9.2 Hz), 3.50 (1H, d, J=9.1 Hz), 3.59 (1H, d, J=9.1 Hz), 4.49 (1H, d, J=6.5 Hz), 4.51 (1H, d, J=6.5 Hz), 4.53 (1H, d, J=6.5 Hz), 4.55 (1H, d, J=6.5 Hz), 7.10 (2H, d, J=8.4 Hz), 7.23 (2H, d, J=8.4 Hz).

(4) Synthesis of 5-(4-chlorobenzyl)-2,2-bis-methoxymethoxymethyl-1-[1,2,4]triazol-1-ylmethylcyclopentanol (Compound (XXIV), G²=CH₂OCH₃, Ym=4-Cl, A=N)

[1,2,4]-Triazole sodium salt (526 mg, 5.78 mmol) was dissolved in NMP (3 ml), and heated to an internal temperature of 115 degrees C. To this, 1 ml of a solution of 5-chlorobenzyl-2,2-bis-methoxymethoxymethyl-cyclopentanone (Compound No. (Compound (XXII), G²=CH₂OCH₃, Ym=4-Cl) 1.374 g (3.85 mmol) in NMP was added. To this solution, sodium t-butoxide 333 mg (3.47 mmol) and TMSOB 1.193 g (6.87 mmol) were added in portions while conducting the reaction at 115 degrees C. for 5 hours. After completion of the reaction, the reaction solution was cooled to 35 degrees C., combined with 15 ml of water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate. The solvent was distilled away and the residue was subjected to silica gel column chromatography (eluent; ethyl acetate) for purification to obtain the desired substance.

Product: 680.2 mg

Yield: 40.2%

Description: Colorless viscous liquid

¹H-NMR (CDCl₃) delta:

1.47-1.56 (1H, m), 1.60-1.80 (2H, m), 1.73-1.83 (1H, m), 2.17 (1H, dd, J=13.2, 4.0 Hz), 2.22-2.31 (1H, m), 2.44 (1H, dd, J=13.2, 10.3 Hz), 3.31 (3H, s), 3.33 (1H, d, J=9.7 Hz), 3.38 (3H, s), 3.46 (1H, d, J=9.7 Hz), 3.59 (2H, s), 4.32 (1H, d, J=14.2 Hz), 4.41 (1H, s), 4.45 (1H, d, J=6.4 Hz), 4.48 (1H, d, J=6.4 Hz), 4.54 (1H, d, J=14.2 Hz), 4.64 (2H, s), 7.04 (2H, d, J=8.4 Hz), 7.21 (2H, d, J=8.4 Hz), 7.95 (1H, s), 8.24 (1H, s).

(5) Synthesis of cis-5-(4-chlorobenzyl)-2,2-bis-hydroxymethyl-1-[1,2,4]triazol-1-ylmethylcyclopentanol (Compound (XIX), Ym=4-Cl, A=N)

5-(4-Chlorobenzyl)-2,2-bis-methoxymethoxymethyl-1-[1,2,4]triazol-1-ylmethylcyclo pentanol (Compound No. (XXIV)-1 (Compound (XXIV), G²=CH₂OCH₃, Ym=4-Cl, A=N) (403 mg, 0.916 mmol) was dissolved in a 10% methanol solution of hydrogen chloride (8 ml), and stirring was conducted at room temperature for 23 hours. After completion of the reaction, the solvent was distilled away, and the residue was combined with water. To this suspension, 2 mol/l aqueous solution of sodium hydroxide was added for neutralization, and stirring was conducted at room temperature for 15 minutes. The crystal was recovered by filtration and dried in vacuum to obtain the desired substance.

Product: 271.1 mg

Yield: 84.1%

Description: White solid

¹H-NMR (400 MHz, CDCl₃) delta:

1.20-1.25 (1H, m), 1.43-1.61 (5H, m), 2.05-2.15 (2H, m), 2.40-2.48 (1H, m), 3.63 (1H, d, J=11.2 Hz), 3.75 (1H, d, J=14.0 Hz), 3.77 (1H, d, J=14.0 Hz), 3.86 (1H, d, J=11.2 Hz), 4.45 (1H, d, J=14.3 Hz), 4.75 (1H, d, J=14.3 Hz), 4.84 (1H, brs), 6.97 (2H, d, J=8.4 Hz), 7.20 (2H, d, J=8.4 Hz), 8.00 (1H, s), 8.24 (1H, s).

The followings are Formulation Examples and Experimental Examples. Carriers (diluents) and auxiliary agents, as well as the mixing ratio thereof for active ingredients may vary within a wide range. “Parts” in each Formulation Example mean “parts by weight”.

Formulation Example 1 Wettable Formulation

Compound (I-1) 50 parts

Lignin sulfonate 5 parts

Alkyl sulfonate 3 parts

Diatomaceous earth 42 parts

are ground and mixed to form a wettable formulation, which is used as being diluted in water.

Formulation Example 2 Powder Formulation

Compound (I-1) 3 parts

Clay 40 parts

Talc 57 parts

are ground and mixed, and used as a dusting formulation.

Formulation Example 3 Granule Formulation

Compound (I-1) 5 parts

Bentonite 43 parts

Clay 45 parts

Lignin sulfonate 7 parts

are mixed uniformly, combined with water and further kneaded, and subjected to an extruding granulator to obtain a granule, which is dried and used as a granule formulation.

Formulation Example 4 Emulsion Formulation

Compound (I-1) 20 parts

Polyoxyethylene alkylaryl ether 10 parts

Polyoxyethylene sorbitan monolaurate 3 parts

Xylene 67 parts

are mixed and dissolved uniformly to obtain an emulsion.

Experimental Example 1 Efficacy Test Against Cucumber Gray Mold

Onto a cucumber (variety:SHARP1) plant in its cotyledon phase grown using a square plastic pot (6 cm×6 cm), a wettable formulation such as Formulation Example 1 which was diluted and suspended in water at a certain concentrations (100 mg/L and 50 mg/L) was sprayed at a rate of 1,000 L/ha. The sprayed leaves were air-dried, and loaded with a paper disc (8 mm in diameter) soaked in a spore suspension of Botrytis cinerea, and kept at 20 degrees C. and a high humidity. Four days after inoculation, the cucumber gray mold lesion degree was investigated, and the protective value was calculated by the following equation. Protective value (%)=(1−mean lesion degree in sprayed plot/mean lesion degree in unsprayed plot)×100

TABLE 21 Lesion degree % Area of onset 0 No Onset 0.5 % Area of lesion spot <5% 1  5% ≦ % Area of lesion spot <10% 2 10% ≦ % Area of lesion spot <25% 3 25% ≦ % Area of lesion spot <50% 4 50% ≦ % Area of lesion spot <80% 5 80% ≦ % Area of lesion spot

In the test described above, Compounds I-1, I-15, I-25, I-65, I-73, I-74, I-77, I-80, I-86, I-88, I-97, I-101, I-104, I-203, I-601, I-602 for example, showed protective values of 80% or higher at 100 mg/L. Furthermore, compounds I-1, I-15, I-73, I-74, I-77, I-80, I-86, I-88, I-97, I-101, I-104, I-203, I-601, I-602 for example, showed protective values of 80% or higher at 50 mg/L.

Experimental Example 2 Efficacy Test Against Wheat Brown Rust

Onto a wheat plant (variety: NORIN No. 61) grown to the two-leaf phase using a square plastic pot (6 cm×6 cm), a wettable formulation such as Formulation Example 1 which was diluted and suspended in water at a certain concentration (100 mg/L and 10 mg/L) was sprayed at a rate of 1,000 L/ha. The sprayed leaves were air-dried, and inoculated with spore suspension of Puccinia recondita (adjusted at 200 spores/vision, Gramin S was added at 60 ppm) by spraying, and kept at 25 degrees C. and a high humidity for 48 hours. Thereafter, the plant was kept in a greenhouse. Nine to 14 days after inoculation, the wheat brown rust lesion degree was investigated, and the protective value was calculated by the following equation. Protective value (%)=(1−lesion degree in sprayed plot/lesion degree in unsprayed plot)×100

TABLE 22 Leaf rust damage scale by Peterson Lesion degree % Area of onset 0 No onset 0.5 Less than 1% 1  1% or higher and less than 5% 2  5% or higher and less than 10% 3 10% or higher and less than 30% 4 30% or higher and less than 50% 5 50% or higher

In the test described above, Compounds I-1, I-15, I-25, I-36, I-65, I-73, I-74, I-77, I-79, I-80, I-82, I-86, I-88, I-97, I-101, I-104, I-115, I-203, I-244, I-301, I-601, I-602 for example, showed protective values of 90% or higher at 100 mg/L. Furthermore, compounds I-1, I-15, I-25, I-36, I-73, I-74, I-77, I-79, I-80, I-86, I-88, I-97, I-101, I-104, I-203, I-601, I-602 for example, showed higher efficacy than that of compound (1) described in [0404] at 10 mg/L.

Experimental Example 3 Efficacy Test Against Wheat fusarium Head Blight

Onto a head of a wheat plant (variety: NORIN No. 61) grown to the blooming phase, a wettable formulations such as Formulation Example 1 which was diluted and suspended in water at certain concentrations (500 mg/L and 100 mg/L) was sprayed at a rate of 1,000 L/ha. The head was air-dried, and inoculated with spore suspension of Fusarium graminearum (adjusted at 2×10⁵ spores/ml, containing Gramin S at a final concentration of 60 ppm and sucrose at a final concentration of 0.5%) by spraying, and kept at 20 degrees C. and a high humidity. Four to 7 days after inoculation, the wheat fusarium head blight lesion degree was investigated, and the protective value was calculated by the following equation. Protective value (%)=(1−lesion degree in sprayed plot/lesion degree in unsprayed plot)×100

TABLE 23 Lesion degree % Area of onset 0 No onset 0.2 Less than 1% 0.5  1% or higher and less than 3% 1  3% or higher and less than 5% 2  5% or higher and less than 10% 3 10% or higher and less than 25% 4 25% or higher and less than 50% 5 50% or higher

In the assay described above, Compounds I-1, I-15, I-25, I-36, I-65, I-73, I-74, I-77, I-79, I-80, I-82, I-86, I-88, I-97, I-101, I-104, I-115, I-174, I-203, I-244, I-301, I-365, I-374, I-401, I-601, I-602 for example, showed protective values of 90% or higher at 500 mg/L. Furthermore, compounds I-1, I-25, I-36, I-73, I-74, I-77, I-80, I-86, I-88, I-101, I-104, I-115, I-601, I-602 for example, showed protective values of 80% or higher at 100 mg/L.

Experimental Example 4 Microplate Test of Biocidal Effect on Wheat Septoria Blotch (Septoria tritici)

A spore suspension of wheat Septoria blotch (Septoria tritici) (spore concentration: 1×10⁶ cells/ml) was prepared, and subjected to 100-fold dilution with a PD medium. A flat 96-well microplate was provided and 1 microliter of the test compound solution formed by dissolution in dimethyl sulfoxide (DMSO) at a concentration 100 times the test concentration was dispensed to the microplate, and then 100 microliter of the medium containing the spore was added and stirred thoroughly. A non-inoculated control zone was provided by adding 1 microliter of DMSO, and after cultivating at 20 degrees C. for about 10 days, the absorbance (550 nm) was measured and % mycelium growth inhibitions were calculated according to the following equation to obtain the activity level (EC₈₀). R=100×(dc−dt)/dc:

R: % mycelium growth inhibition

dc: Absorbance of non-treatment zone

dt: Absorbance of treatment zone

With regard to the activity level (EC₈₀), I-1, I-15, I-25, I-36, I-73, I-74, I-77, I-79, I-80, I-86, I-88, I-97, I-101, I-104, I-203, I-244, I-301, I-601, I-602 for example, showed an activity level as high as 0.2 mg/L or less, in contrast to the following comparative compound (I) described in Patent Literature 1 (JPA01-93574) whose activity was 0.4 mg/L.

Comparative Compound (1) (1RS,5SR)-5-(4-chlorobenzyl)-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol

Experimental Example 5 Assay for Fungicidal Effect on Various Pathogenic Microorganism and Hazardous Microorganisms

In this Experimental Example, the fungicidal effects of the inventive compounds on various phytopathogenic fungi for plants and hazardous microorganism for industrial materials were examined by the methods described below.

Each inventive compound was dissolved in 2 ml of dimethyl sulfoxide. 0.6 ml of this solution was added to 60 nil of a PDA medium (potato dextrose agar medium) at about 60 degrees C., which was mixed thoroughly in a 100-ml conical flask, and poured into a dish, where it was solidified, thereby obtaining a plate medium containing the inventive compound at 50 mg/L and 5 mg/L.

On the other hand, a subject microorganism previously cultured on a plate medium was cut out using a cork borer whose diameter was 4 mm, and inoculated to the test compound-containing plate medium described above. After inoculation, the dish was grown at the optimum growth temperatures for respective microorganisms (for this growth temperature, see, for example, a reference LIST OF CULTURES 1996 microorganisms 10th edition, Institute for Fermentation (foundation)) for 1 to 3 days, and the mycelial growth was measured as a diameter of its flora. The growth degree of the microorganism on the test compound-containing plate medium thus observed was compared with the growth degree of the microorganism in the untreated group, and % mycelial growth inhibition was calculated by the following equation. R=100(dc−dt)/dc

wherein R=% mycelial extension inhibition, dc=flora diameter in untreated plate, dt=flora diameter in treated plate.

The results obtained as described above were evaluated as one of the 5 grades according to the following criteria.

<Growth Inhibition Grade>

-   -   5: % Mycerial growth inhibition of 80% or higher     -   4: % Mycerial growth inhibition of less than 80 to 60% or higher     -   3: % Mycelial growth inhibition of less than 60 to 40% or higher     -   2: % Mycerial growth inhibition of less than 40 to 20% or higher     -   1: % Mycerial growth inhibition of less than 20%

TABLE 24-1 Concentration Compound No. (mg/L) P.n P.h F.g U.n P.o G.f A.m S.s B.c F.c R.sec I-1 50 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 I-15 50 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 I-25 50 5 5 5 5 5 5 5 5 5 5 5 5 4 3 5 3 5 5 4 5 5 5 5 I-36 50 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 4 5 5 5 5 4 5 5 I-65 50 5 5 5 5 5 5 5 5 5 5 5 5 4 3 4 3 3 4 3 3 4 3 3 I-73 50 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 I-74 50 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 4 5 5 5 5 I-77 50 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 I-79 50 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 I-80 50 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 I-82 50 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 I-86 50 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 4 5 5 5 5 I-88 50 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 4 5 5 5 5 I-97 50 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 4 5 5 5 5 I-101 50 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5

TABLE 24-2 Concentration Compound No. (mg/L) P.n P.h F.g U.n P.o G.f A.m S.s B.c F.c R.sec I-104 50 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 I-115 50 5 5 5 5 5 5 5 5 5 5 5 5 4 5 5 4 5 5 5 5 5 5 5 I-174 50 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 4 5 5 5 5 5 5 5 I-203 50 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 I-244 50 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 4 5 5 I-301 50 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 I-365 50 5 5 5 5 5 5 5 5 5 5 5 5 3 2 2 2 1 1 2 2 1 2 2 I-374 50 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 4 5 5 4 5 5 5 5 I-401 50 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 4 5 5 4 5 5 5 5 I-601 50 5 5 5 5 5 5 5 5 5 5 5 5 4 4 5 3 5 5 4 5 4 5 5 I-602 50 5 5 5 5 5 5 5 5 5 5 5 5 3 3 5 4 5 5 4 5 4 5 5

TABLE 24-3 Concentration Compound No. (mg/L) P.n P.h F.g U.n P.o G.f A.m S.s B.c F.c R.sec I-1 50 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 I-73 50 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 I-77 50 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 compound (2) 50 4 4 5 3 4 4 4 5 5 4 5 5 3 2 3 1 4 3 4 3 2 3 5

Wheat Septoria nodorum blotch (Phaeosphaeria nodorum) P.n

Wheat eye spot (Pseudocercoporella herpotrichoides) P.h

Wheat fusarium blight (Fusarium graminearum) F.g

Barley loose smut (Ustilago nuda) U.n

Rice blast (Pyricularia oryzae) P.o

Rice bakanae disease (Giberella fujikuroi) G.f

Alternaria blotch (Alternaria alternata) A.m

Sclerotinia rot (Sclerotinia sclerotiorum) S.s

Gray mold (Botritis cinerea) B.c

Cucumber fusarium wilt (Fusarium oxysporum) F.c

Barley leaf blotch (Rhynchosporium secalis) R.sec

Comparative Compound (2)

Also in the experiments with the treatment at 50 mg/l against a microorganism which deteriorates paper, pulp, fiber, leather, paint and the like, namely, Aspergillus microorganism (Aspergillus sp.), Tricoderma microorganism (Trichoderma sp.), penicillium microorganism (Penicillium sp.), Cladosporium microorganism (Cladosporium sp.), Mucor microorganism (Mucor sp.), Aureobasidium microorganism (Aureobasidium sp.), Curvularia microorganism (Curvularia sp.), a wood denaturing microorganism Oouzuratake (Tyromyces palustris) and Kawaratake, (Coriolus versicolor), Compounds I-1, I-15, I-25, I-36, I-65, I-73, I-74, I-77, I-80, I-82, I-86, I-88, I-97, I-101, I-104, I-115, I-174, I-203, I-244, I-301, I-365, I-401, I-601, I-602 showed growth inhibition grades as high as 4.

Experimental Example 6 Rice Elongation Prevention Assay

36 mg of a test compound was dissolved in 3.6 ml of DMSO, and applied to 180 g of rice seeds in a vial. After soaking the seeds and promoting germination, the seeds were seeded to seedling boxes at a rate of 180 g/box, allowed to germinate in the seedling boxes, and then cultivated in a greenhouse at 35 degrees C. 20 Days after seeding, the plant height of the seedlings in each treatment group was surveyed in 10 locations, and the % plant height suppression was calculated by the following Equation 6. R=100(hc−ht)/hc

-   -   wherein R=% Plant     -   height suppression, hc=Mean untreated plant height, ht=mean         treated plant height.

The results obtained above were assigned to one of the following 5 grades of the growth regulation.

<Growth Regulation Grade>

5: % Plant height suppression of 50% or higher

4: % Plant height suppression of less than 50 to 30% or higher

3: % Plant height suppression of less than 30 to 20% or higher

2: % Plant height suppression of less than 20 to 10% or higher

1: % Plant height suppression of 10% or less

In the assay described above, Compounds I-1, I-15, I-25, I-36, I-65, I-73, I-74, I-77, I-80, I-82, I-86, I-88, I-97, I-101, I-104, I-115, I-203, I-244, I-301, I-365, I-374, I-401, I-601, I-602 showed growth regulation grades of 4 or higher in the growth of rice plant.

Experimental Example 7 Assay for Fungicidal Effect on Septoria tritici

In this Experimental Example, the fungicidal effects of the inventive compounds on a phytopathogenic fungi, Septoria tritici were examined and compared to the Comparative Compound (3) described in Patent Literature 1 (JPA01-93574) by the methods described below.

Comparative Compound (3) (1RS,5SR)-5-(4-fluorobenzyl)-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol

Each inventive compound was dissolved in 2 ml of dimethyl sulfoxide to obtain a prescribed concentration. 0.6 ml of the each solution was added to 60 ml of a PDA medium (potato dextrose agar medium) at about 60 degrees C., which was mixed thoroughly in a 100-ml conical flask, and poured into a dish, where it was solidified, thereby obtaining medium plates containing the inventive compound at 0.02 mg/L.

The subject microorganism previously cultured on a plate medium was cut out using a cork borer whose diameter was 4 mm, and inoculated to the test compound-containing plate medium described above. After inoculation, the dish was incubated at the optimum growth temperatures for the microorganism (for this growth temperature, see, for example, a reference LIST OF CULTURES 1996 microorganisms 10th edition, Institute for Fermentation (foundation)) for 10 days, and the mycelial growth was measured as a diameter of its flora. The growth degree of the microorganism on the test compound-containing plate medium thus observed was compared with the growth degree of the microorganism in the untreated group, and % mycelial growth inhibition was calculated by the following equation. R=100(dc−dt)/dc

wherein R=% mycelial extension inhibition, dc=flora diameter in untreated plate, dt=flora diameter in treated plate.

The results obtained as described above were evaluated as one of the 5 grades according to the following criteria.

<Growth Inhibition Grade>

5: % Mycerial growth inhibition of 80% or higher

4: % Mycerial growth inhibition of less than 80 to 60% or higher

3: % Mycerial growth inhibition of less than 60 to 40% or higher

2: % Mycerial growth inhibition of less than 40 to 20% or higher

1: % Mycerial growth inhibition of less than 20%

In the test described above, following results were obtained.

TABLE 25 Concentration Compound No. mg/L grade I-73 0.02 5 I-77 0.02 5 Compound (3) 0.02 2

Experimental Example 8 Efficacy Test Against Wheat Brown Rust

Onto a wheat plant (variety: NORIN No. 61) grown to the two-leaf phase using a square plastic pot (6 cm×6 cm), a wettable formulation such as Formulation Example 1 which was diluted and suspended in water at a certain concentration (2 mg/L) was sprayed at a rate of 1,000 L/ha. The sprayed leaves were air-dried, and inoculated with spore suspension of Puccinia recondita (adjusted at 200 spores/vision, Gramin S was added at 60 ppm) by spraying, and kept at 25 degrees C. and a high humidity for 48 hours. Thereafter, the plant was kept in a greenhouse. Nine to 14 days after inoculation, the wheat brown rust lesion degree was investigated, and the protective value was calculated by the following equation. Protective value (%)=(1−lesion degree in sprayed plot/lesion degree in unsprayed plot)×100

TABLE 26 Leaf rust damage scale by Peterson Lesion degree % Area of onset 0 No onset 0.5 Less than 1% 1  1% or higher and less than 5% 2  5% or higher and less than 10% 3 10% or higher and less than 30% 4 30% or higher and less than 50% 5 50% or higher

In the test described above, following results were obtained.

TABLE 27 Concentration Compound No. mg/L degree I-77 0.02 0 Compound (3) 0.02 3

Experimental Example 9 Assay for Fungicidal Effect on Septoria tritici

In this Experimental Example, the fungicidal effects of the inventive compounds on Septoria tritici were examined by the methods described in the Experimental Example 5. In this Experimental Example, the inventive compounds were diluted at 1.25 mg/L.

TABLE 28 Concentration Compound No. (mg/L) growth inhibition grade I-1 1.25 5 I-73 1.25 5 I-77 1.25 5 I-88 1.25 5 compound (1) 1.25 3 compound (2) 1.25 1

Experimental Example 10 Efficacy Test Against Wheat Brown Rust

In this Experimental Example, the wheat brown rust lesion degree was investigated by the methods described in the Experimental Example 2. In this Experimental Example, the inventive compounds were diluted at 1 mg/L and sprayed at a rate of 1,000 L/ha.

TABLE 29 Concentration Compound No. (g/ha) lesion degree I-1 1 0.5 I-73 1 0.5 I-77 1 0.5 I-88 1 0.5 compound (1) 1 3 compound (2) 1 5

INDUSTRIAL APPLICABILITY

An azole derivative according to the invention can preferably be utilized as an active ingredient of agro-horticultural bactericides, plant growth regulators and industrial material protecting agents. 

The invention claimed is:
 1. A compound represented by Formula (XI):

wherein R¹ denotes a C₁-C₆ alkyl group, a C₂-C₆ alkenyl group or a C₂-C₆ alkynyl group; R² denotes a C₁-C₄ alkyl group; each Y denotes a halogen atom, a C₁-C₄ alkyl group, a C₁-C₄ haloalkyl group, a C₁-C₄ alkoxy group, a C₁-C₄ haloalkoxy group, a phenyl group, a cyano group or a nitro group; and m denotes 0 to 5; when m is 2 or more, each Y may be same or different. 